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Sample records for charged sodium channel

  1. S1-S3 counter charges in the voltage sensor module of a mammalian sodium channel regulate fast inactivation.

    Science.gov (United States)

    Groome, James R; Winston, Vern

    2013-05-01

    The movement of positively charged S4 segments through the electric field drives the voltage-dependent gating of ion channels. Studies of prokaryotic sodium channels provide a mechanistic view of activation facilitated by electrostatic interactions of negatively charged residues in S1 and S2 segments, with positive counterparts in the S4 segment. In mammalian sodium channels, S4 segments promote domain-specific functions that include activation and several forms of inactivation. We tested the idea that S1-S3 countercharges regulate eukaryotic sodium channel functions, including fast inactivation. Using structural data provided by bacterial channels, we constructed homology models of the S1-S4 voltage sensor module (VSM) for each domain of the mammalian skeletal muscle sodium channel hNaV1.4. These show that side chains of putative countercharges in hNaV1.4 are oriented toward the positive charge complement of S4. We used mutagenesis to define the roles of conserved residues in the extracellular negative charge cluster (ENC), hydrophobic charge region (HCR), and intracellular negative charge cluster (INC). Activation was inhibited with charge-reversing VSM mutations in domains I-III. Charge reversal of ENC residues in domains III (E1051R, D1069K) and IV (E1373K, N1389K) destabilized fast inactivation by decreasing its probability, slowing entry, and accelerating recovery. Several INC mutations increased inactivation from closed states and slowed recovery. Our results extend the functional characterization of VSM countercharges to fast inactivation, and support the premise that these residues play a critical role in domain-specific gating transitions for a mammalian sodium channel.

  2. Insect sodium channels and insecticide resistance

    OpenAIRE

    Dong, Ke

    2007-01-01

    Voltage-gated sodium channels are essential for the generation and propagation of action potentials (i.e., electrical impulses) in excitable cells. Although most of our knowledge about sodium channels is derived from decades of studies of mammalian isoforms, research on insect sodium channels is revealing both common and unique aspects of sodium channel biology. In particular, our understanding of the molecular dynamics and pharmacology of insect sodium channels has advanced greatly in recent...

  3. Lipid Regulation of Sodium Channels.

    Science.gov (United States)

    D'Avanzo, N

    2016-01-01

    The lipid landscapes of cellular membranes are complex and dynamic, are tissue dependent, and can change with the age and the development of a variety of diseases. Researchers are now gaining new appreciation for the regulation of ion channel proteins by the membrane lipids in which they are embedded. Thus, as membrane lipids change, for example, during the development of disease, it is likely that the ionic currents that conduct through the ion channels embedded in these membranes will also be altered. This chapter provides an overview of the complex regulation of prokaryotic and eukaryotic voltage-dependent sodium (Nav) channels by fatty acids, sterols, glycerophospholipids, sphingolipids, and cannabinoids. The impact of lipid regulation on channel gating kinetics, voltage-dependence, trafficking, toxin binding, and structure are explored for Nav channels that have been examined in heterologous expression systems, native tissue, and reconstituted into artificial membranes. Putative mechanisms for Nav regulation by lipids are also discussed. PMID:27586290

  4. Sodium Channel Inhibiting Marine Toxins

    Science.gov (United States)

    Llewellyn, Lyndon E.

    Saxitoxin (STX), tetrodotoxin (TTX) and their many chemical relatives are part of our daily lives. From killing people who eat seafood containing these toxins, to being valuable research tools unveiling the invisible structures of their pharmacological receptor, their global impact is beyond measure. The pharmacological receptor for these toxins is the voltage-gated sodium channel which transports Na ions between the exterior to the interior of cells. The two structurally divergent families of STX and TTX analogues bind at the same location on these Na channels to stop the flow of ions. This can affect nerves, muscles and biological senses of most animals. It is through these and other toxins that we have developed much of our fundamental understanding of the Na channel and its part in generating action potentials in excitable cells.

  5. Sodium channels, inherited epilepsy, and antiepileptic drugs.

    Science.gov (United States)

    Catterall, William A

    2014-01-01

    Voltage-gated sodium channels initiate action potentials in brain neurons, mutations in sodium channels cause inherited forms of epilepsy, and sodium channel blockers-along with other classes of drugs-are used in therapy of epilepsy. A mammalian voltage-gated sodium channel is a complex containing a large, pore-forming α subunit and one or two smaller β subunits. Extensive structure-function studies have revealed many aspects of the molecular basis for sodium channel structure, and X-ray crystallography of ancestral bacterial sodium channels has given insight into their three-dimensional structure. Mutations in sodium channel α and β subunits are responsible for genetic epilepsy syndromes with a wide range of severity, including generalized epilepsy with febrile seizures plus (GEFS+), Dravet syndrome, and benign familial neonatal-infantile seizures. These seizure syndromes are treated with antiepileptic drugs that offer differing degrees of success. The recent advances in understanding of disease mechanisms and sodium channel structure promise to yield improved therapeutic approaches. PMID:24392695

  6. Bioinspired Artificial Sodium and Potassium Ion Channels.

    Science.gov (United States)

    Rodríguez-Vázquez, Nuria; Fuertes, Alberto; Amorín, Manuel; Granja, Juan R

    2016-01-01

    In Nature, all biological systems present a high level of compartmentalization in order to carry out a wide variety of functions in a very specific way. Hence, they need ways to be connected with the environment for communication, homeostasis equilibrium, nutrition, waste elimination, etc. The biological membranes carry out these functions; they consist of physical insulating barriers constituted mainly by phospholipids. These amphipathic molecules spontaneously aggregate in water to form bilayers in which the polar groups are exposed to the aqueous media while the non-polar chains self-organize by aggregating to each other to stay away from the aqueous media. The insulating properties of membranes are due to the formation of a hydrophobic bilayer covered at both sides by the hydrophilic phosphate groups. Thus, lipophilic molecules can permeate the membrane freely, while the small charged or very hydrophilic molecules require the assistance of other membrane components in order to overcome the energetic cost implied in crossing the non-polar region of the bilayer. Most of the large polar species (such as oligosaccharides, polypeptides or nucleic acids) cross into and out of the cell via endocytosis and exocytosis, respectively. Nature has created a series of systems (carriers and pores) in order to control the balance of small hydrophilic molecules and ions. The most important structures to achieve these goals are the ionophoric proteins that include the channel proteins, such as the sodium and potassium channels, and ionic transporters, including the sodium/potassium pumps or calcium/sodium exchangers among others. Inspired by these, scientists have created non-natural synthetic transporting structures to mimic the natural systems. The progress in the last years has been remarkable regarding the efficient transport of Na(+) and K(+) ions, despite the fact that the selectivity and the ON/OFF state of the non-natural systems remain a present and future challenge

  7. Functional Expression of an Arachnid Sodium Channel Reveals Residues Responsible for Tetrodotoxin Resistance in Invertebrate Sodium Channels*

    OpenAIRE

    Du, Yuzhe; Nomura, Yoshiko; Liu, Zhiqi; Huang, Zachary Y.; Dong, Ke

    2009-01-01

    Tetrodotoxin (TTX) is a potent blocker of voltage-gated sodium channels, but not all sodium channels are equally sensitive to inhibition by TTX. The molecular basis of differential TTX sensitivity of mammalian sodium channels has been largely elucidated. In contrast, our knowledge about the sensitivity of invertebrate sodium channels to TTX remains poor, in part because of limited success in functional expression of these channels. In this study, we report the functional characterization in X...

  8. Understanding Sodium Channel Function and Modulation Using Atomistic Simulations of Bacterial Channel Structures.

    Science.gov (United States)

    Boiteux, C; Allen, T W

    2016-01-01

    Sodium channels are chief proteins involved in electrical signaling in the nervous system, enabling critical functions like heartbeat and brain activity. New high-resolution X-ray structures for bacterial sodium channels have created an opportunity to see how these proteins operate at the molecular level. An important challenge to overcome is establishing relationships between the structures and functions of mammalian and bacterial channels. Bacterial sodium channels are known to exhibit the main structural features of their mammalian counterparts, as well as several key functional characteristics, including selective ion conduction, voltage-dependent gating, pore-based inactivation and modulation by local anesthetic, antiarrhythmic and antiepileptic drugs. Simulations have begun to shed light on each of these features in the past few years. Despite deviations in selectivity signatures for bacterial and mammalian channels, simulations have uncovered the nature of the multiion conduction mechanism associated with Na(+) binding to a high-field strength site established by charged glutamate side chains. Simulations demonstrated a surprising level of flexibility of the protein, showing that these side chains are active participants in the permeation process. They have also uncovered changes in protein structure, leading to asymmetrical collapses of the activation gate that have been proposed to correspond to inactivated structures. These observations offer the potential to examine the mechanisms of state-dependent drug activity, focusing on pore-blocking and pore-based slow inactivation in bacterial channels, without the complexities of inactivation on multiple timescales seen in eukaryotic channels. Simulations have provided molecular views of the interactions of drugs, consistent with sites predicted in mammalian channels, as well as a wealth of other sites as potential new drug targets. In this chapter, we survey the new insights into sodium channel function that

  9. Molecular determinants on the insect sodium channel for the specific action of type II pyrethroid insecticides.

    Science.gov (United States)

    Du, Yuzhe; Nomura, Yoshiko; Luo, Ningguang; Liu, Zhiqi; Lee, Jung-Eun; Khambay, Bhupinder; Dong, Ke

    2009-01-15

    Pyrethroid insecticides are classified as type I or type II based on their distinct symptomology and effects on sodium channel gating. Structurally, type II pyrethroids possess an alpha-cyano group at the phenylbenzyl alcohol position, which is lacking in type I pyrethroids. Both type I and type II pyrethroids inhibit deactivation consequently prolonging the opening of sodium channels. However, type II pyrethroids inhibit the deactivation of sodium channels to a greater extent than type I pyrethroids inducing much slower decaying of tail currents upon repolarization. The molecular basis of a type II-specific action, however, is not known. Here we report the identification of a residue G(1111) and two positively charged lysines immediately downstream of G(1111) in the intracellular linker connecting domains II and III of the cockroach sodium channel that are specifically involved in the action of type II pyrethroids, but not in the action of type I pyrethroids. Deletion of G(1111), a consequence of alternative splicing, reduced the sodium channel sensitivity to type II pyrethroids, but had no effect on channel sensitivity to type I pyrethroids. Interestingly, charge neutralization or charge reversal of two positively charged lysines (Ks) downstream of G(1111) had a similar effect. These results provide the molecular insight into the type II-specific interaction of pyrethroids with the sodium channel at the molecular level.

  10. On conduction in a bacterial sodium channel.

    Directory of Open Access Journals (Sweden)

    Simone Furini

    Full Text Available Voltage-gated Na⁺-channels are transmembrane proteins that are responsible for the fast depolarizing phase of the action potential in nerve and muscular cells. Selective permeability of Na⁺ over Ca²⁺ or K⁺ ions is essential for the biological function of Na⁺-channels. After the emergence of the first high-resolution structure of a Na⁺-channel, an anionic coordination site was proposed to confer Na⁺ selectivity through partial dehydration of Na⁺ via its direct interaction with conserved glutamate side chains. By combining molecular dynamics simulations and free-energy calculations, a low-energy permeation pathway for Na⁺ ion translocation through the selectivity filter of the recently determined crystal structure of a prokaryotic sodium channel from Arcobacter butzleri is characterised. The picture that emerges is that of a pore preferentially occupied by two ions, which can switch between different configurations by crossing low free-energy barriers. In contrast to K⁺-channels, the movements of the ions appear to be weakly coupled in Na⁺-channels. When the free-energy maps for Na⁺ and K⁺ ions are compared, a selective site is characterised in the narrowest region of the filter, where a hydrated Na⁺ ion, and not a hydrated K⁺ ion, is energetically stable.

  11. Shaped charge with an axial channel

    Science.gov (United States)

    Malygin, A. V.; Proskuryakov, E. V.; Sorokin, M. V.; Fomin, V. M.

    2011-05-01

    A shaped charge with an axial channel is considered. The charge is initiated by an impact of an annular plate. As a result, the shaped charge is initiated at all points of the domain shaped as a ring. The impact plate material and parameters (velocity, thickness, width, and distance covered by the plate) that ensure stable penetration of the shaped charge are determined. The results obtained can be used to develop a composite (e.g., "tandem") shaped charge of the "base-head" type (the charge located farther from the target is first initiated, followed by initiation of the charge located closer to the target).

  12. Sodium Channel (Dys)Function and Cardiac Arrhythmias

    NARCIS (Netherlands)

    C.A. Remme; C.R. Bezzina

    2010-01-01

    P>Cardiac voltage-gated sodium channels are transmembrane proteins located in the cell membrane of cardiomyocytes. Influx of sodium ions through these ion channels is responsible for the initial fast upstroke of the cardiac action potential. This inward sodium current thus triggers the initiation an

  13. DDESC: Dragon database for exploration of sodium channels in human

    Directory of Open Access Journals (Sweden)

    Radovanovic Aleksandar

    2008-12-01

    Full Text Available Abstract Background Sodium channels are heteromultimeric, integral membrane proteins that belong to a superfamily of ion channels. The mutations in genes encoding for sodium channel proteins have been linked with several inherited genetic disorders such as febrile epilepsy, Brugada syndrome, ventricular fibrillation, long QT syndrome, or channelopathy associated insensitivity to pain. In spite of these significant effects that sodium channel proteins/genes could have on human health, there is no publicly available resource focused on sodium channels that would support exploration of the sodium channel related information. Results We report here Dragon Database for Exploration of Sodium Channels in Human (DDESC, which provides comprehensive information related to sodium channels regarding different entities, such as "genes and proteins", "metabolites and enzymes", "toxins", "chemicals with pharmacological effects", "disease concepts", "human anatomy", "pathways and pathway reactions" and their potential links. DDESC is compiled based on text- and data-mining. It allows users to explore potential associations between different entities related to sodium channels in human, as well as to automatically generate novel hypotheses. Conclusion DDESC is first publicly available resource where the information related to sodium channels in human can be explored at different levels. This database is freely accessible for academic and non-profit users via the worldwide web http://apps.sanbi.ac.za/ddesc.

  14. Tetrodotoxin-resistant sodium channels in neuropathic pain

    OpenAIRE

    Fjell Hjelmström, Jenny

    2000-01-01

    Injury to the peripheral nervous system can cause neuropathic pain. Abnormal sodium channel activity has been implicated as a source of ectopic firing and changes in nociceptive threshold following nerve injury. Primary sensory neurons exhibit at least two types of sodium currents: rapidly inactivating tetrodotoxin-sensitive (TTX-S) and slowly inactivating TTX-resistant (TTX-R) sodium currents. Two TTX-R sodium channels that are expressed in primary sensory neurons have been...

  15. Multiple Sodium Channel Variants in the Mosquito Culex quinquefasciatus

    OpenAIRE

    He, Lin; Li, Ting; Zhang, Lee; Liu, Nannan

    2012-01-01

    Voltage-gated sodium channels are the target sites of both DDT and pyrethroid insecticides. The importance of alternative splicing as a key mechanism governing the structural and functional diversity of sodium channels and the resulting development of insecticide and acaricide resistance is widely recognized, as shown by the extensive research on characterizing alternative splicing and variants of sodium channels in medically and agriculturally important insect species. Here we present the fi...

  16. Epithelial sodium channel modulates platelet collagen activation.

    Science.gov (United States)

    Cerecedo, Doris; Martínez-Vieyra, Ivette; Alonso-Rangel, Lea; Benítez-Cardoza, Claudia; Ortega, Arturo

    2014-03-01

    Activated platelets adhere to the exposed subendothelial extracellular matrix and undergo a rapid cytoskeletal rearrangement resulting in shape change and release of their intracellular dense and alpha granule contents to avoid hemorrhage. A central step in this process is the elevation of the intracellular Ca(2+) concentration through its release from intracellular stores and on throughout its influx from the extracellular space. The Epithelial sodium channel (ENaC) is a highly selective Na(+) channel involved in mechanosensation, nociception, fluid volume homeostasis, and control of arterial blood pressure. The present study describes the expression, distribution, and participation of ENaC in platelet migration and granule secretion using pharmacological inhibition with amiloride. Our biochemical and confocal analysis in suspended and adhered platelets suggests that ENaC is associated with Intermediate filaments (IF) and with Dystrophin-associated proteins (DAP) via α-syntrophin and β-dystroglycan. Migration assays, quantification of soluble P-selectin, and serotonin release suggest that ENaC is dispensable for migration and alpha and dense granule secretion, whereas Na(+) influx through this channel is fundamental for platelet collagen activation.

  17. Sodium Channel Mutations and Pyrethroid Resistance in Aedes aegypti

    Directory of Open Access Journals (Sweden)

    Yuzhe Du

    2016-10-01

    Full Text Available Pyrethroid insecticides are widely used to control insect pests and human disease vectors. Voltage-gated sodium channels are the primary targets of pyrethroid insecticides. Mutations in the sodium channel have been shown to be responsible for pyrethroid resistance, known as knockdown resistance (kdr, in various insects including mosquitoes. In Aedes aegypti mosquitoes, the principal urban vectors of dengue, zika, and yellow fever viruses, multiple single nucleotide polymorphisms in the sodium channel gene have been found in pyrethroid-resistant populations and some of them have been functionally confirmed to be responsible for kdr in an in vitro expression system, Xenopus oocytes. This mini-review aims to provide an update on the identification and functional characterization of pyrethroid resistance-associated sodium channel mutations from Aedes aegypti. The collection of kdr mutations not only helped us develop molecular markers for resistance monitoring, but also provided valuable information for computational molecular modeling of pyrethroid receptor sites on the sodium channel.

  18. Functional expression of an arachnid sodium channel reveals residues responsible for tetrodotoxin resistance in invertebrate sodium channels.

    Science.gov (United States)

    Du, Yuzhe; Nomura, Yoshiko; Liu, Zhiqi; Huang, Zachary Y; Dong, Ke

    2009-12-01

    Tetrodotoxin (TTX) is a potent blocker of voltage-gated sodium channels, but not all sodium channels are equally sensitive to inhibition by TTX. The molecular basis of differential TTX sensitivity of mammalian sodium channels has been largely elucidated. In contrast, our knowledge about the sensitivity of invertebrate sodium channels to TTX remains poor, in part because of limited success in functional expression of these channels. In this study, we report the functional characterization in Xenopus oocytes of the first non-insect, invertebrate voltage-gated sodium channel from the varroa mite (Varroa destructor), an ecto-parasite of the honeybee. This arachnid sodium channel activates and inactivates rapidly with half-maximal activation at -18 mV and half-maximal fast inactivation at -29 mV. Interestingly, this arachnid channel showed surprising TTX resistance. TTX blocked this channel with an IC(50) of 1 microM. Subsequent site-directed mutagenesis revealed two residues, Thr-1674 and Ser-1967, in the pore-forming region of domains III and IV, respectively, which were responsible for the observed resistance to inhibition by TTX. Furthermore, sequence comparison and additional amino acid substitutions suggested that sequence polymorphisms at these two positions could be a widespread mechanism for modulating TTX sensitivity of sodium channels in diverse invertebrates. PMID:19828457

  19. Inhibition of voltage-gated sodium channels by sumatriptan bioisosteres

    Directory of Open Access Journals (Sweden)

    Roberta eCarbonara

    2015-07-01

    Full Text Available Voltage-gated sodium channels are known to play a pivotal role in perception and transmission of pain sensations. Gain-of-function mutations in the genes encoding the peripheral neuronal sodium channels, hNav1.7-1.9, cause human painful diseases. Thus while treatment of chronic pain remains an unmet clinical need, sodium channel blockers are considered as promising druggable targets. In a previous study, we evaluated the analgesic activity of sumatriptan, an agonist of serotonin 5HT1B/D receptors, and some new chiral bioisosteres, using the hot plate test in the mouse. Interestingly, we observed that the analgesic effectiveness was not necessarily correlated to serotonin agonism. In this study, we evaluated whether sumatriptan and its congeners may inhibit heterologously-expressed hNav1.7 sodium channels using the patch-clamp method. We show that sumatriptan blocks hNav1.7 channels only at very high, supratherapeutic concentrations. In contrast, its three analogues, namely 20b, (R-31b, and (S-22b, exert a dose and use-dependent sodium channel block. At 0.1 and 10 Hz stimulation frequencies, the most potent compound, (S-22b, was 4.4 and 1.7 fold more potent than the well-known sodium channel blocker mexiletine. The compound induces a negative shift of voltage dependence of fast inactivation, suggesting higher affinity to the inactivated channel. Accordingly, we show that (S-22b likely binds the conserved local anesthetic receptor within voltage-gated sodium channels. Combining these results with the previous ones, we hypothesize that use-dependent sodium channel blockade contributes to the analgesic activity of (R-31b and (S-22b. These later compounds represent promising lead compounds for the development of efficient analgesics, the mechanism of action of which may include a dual action on sodium channels and 5HT1D receptors.

  20. Metaflumizone is a novel sodium channel blocker insecticide.

    Science.gov (United States)

    Salgado, V L; Hayashi, J H

    2007-12-15

    Metaflumizone is a novel semicarbazone insecticide, derived chemically from the pyrazoline sodium channel blocker insecticides (SCBIs) discovered at Philips-Duphar in the early 1970s, but with greatly improved mammalian safety. This paper describes studies confirming that the insecticidal action of metaflumizone is due to the state-dependent blockage of sodium channels. Larvae of the moth Spodoptera eridania injected with metaflumizone became paralyzed, concomitant with blockage of all nerve activity. Furthermore, tonic firing of abdominal stretch receptor organs from Spodoptera frugiperda was blocked by metaflumizone applied in the bath, consistent with the block of voltage-dependent sodium channels. Studies on native sodium channels, in primary-cultured neurons isolated from the CNS of the larvae of the moth Manduca sexta and on Para/TipE sodium channels heterologously expressed in Xenopus (African clawed frog) oocytes, confirmed that metaflumizone blocks sodium channels by binding selectively to the slow-inactivated state, which is characteristic of the SCBIs. The results confirm that metaflumizone is a novel sodium channel blocker insecticide. PMID:17959312

  1. Control microprocessor system for charge particle channeling

    International Nuclear Information System (INIS)

    Control microprocessor systems are widely applied not only in designing industrial robots but in providing functioning of different experimental plants. The experiment control system for charge particle channeling has been considered in the paper. Flexibility, relatively low cost and high reliability are advantages of these systems

  2. Asymmetric functional contributions of acidic and aromatic side chains in sodium channel voltage-sensor domains

    DEFF Research Database (Denmark)

    Pless, Stephan Alexander; Elstone, Fisal D; Niciforovic, Ana P;

    2014-01-01

    Voltage-gated sodium (NaV) channels mediate electrical excitability in animals. Despite strong sequence conservation among the voltage-sensor domains (VSDs) of closely related voltage-gated potassium (KV) and NaV channels, the functional contributions of individual side chains in Nav VSDs remain...... largely enigmatic. To this end, natural and unnatural side chain substitutions were made in the S2 hydrophobic core (HC), the extracellular negative charge cluster (ENC), and the intracellular negative charge cluster (INC) of the four VSDs of the skeletal muscle sodium channel isoform (NaV1.......4). The results show that the highly conserved aromatic side chain constituting the S2 HC makes distinct functional contributions in each of the four NaV domains. No obvious cation-pi interaction exists with nearby S4 charges in any domain, and natural and unnatural mutations at these aromatic sites produce...

  3. Charged and Neutral Particles Channeling Phenomena Channeling 2008

    Science.gov (United States)

    Dabagov, Sultan B.; Palumbo, Luigi

    2010-04-01

    On the discovery of coherent Bremsstrahlung in a single crystal at the Frascati National Laboratories / C. Barbiellini, G. P. Murtas and S. B. Dabagov -- Advances in coherent Bremsstrahlung and LPM-effect studies (to the lOOth anniversary from the birth of L. D. Landau) / N. F. Shul'ga -- Spectra of radiation and created particles at intermediate energy in oriented crystal taking into account energy loss / V. N. Baier and V. M. Katkov -- The coherent Bremsstrahlung beam at MAX-lab facility / K. Fissum ... [et al.] -- Radiation from thin, structured targets (CERN NA63) / A. Dizdar -- Hard incoherent radiation in thick crystals / N. F. Shul'ga, V. V. Syshchenko and A. I. Tarnovsky -- Coherent Bremsstrahlung in periodically deformed crystals with a complex base / A. R. Mkrtchyan, A. A. Saharian and V. V. Parazian -- Induction of coherent x-ray Bremsstrahlung in crystals under the influence of acoustic waves / A. R. Mkrtchyan and V. V. Parazian -- Coherent processes in bent single crystals / V. A. Maisheev -- Experimental and theoretical investigation of complete transfer phenomenon for media with various heat exchange coefficients / A. R. Mkrtchyan, A. E. Movsisyan and V. R. Kocharyan -- Coherent pair production in crystals / A. R. Mkrtchyan, A. A. Saharian and V. V. Parazian -- Negative particle planar and axial channeling and channeling collimation / R. A. Carrigan, Jr. -- CERN crystal-based collimation in modern hadron colliders / W. Scandale -- Studies and application of bent crystals for beam steering at 70 GeV IHEP accelerator / A. G. Afonin ... [et al.] -- Crystal collimation studies at the Tevatron (T-980) / N. V. Mokhov ... [et al.] -- Fabrication of crystals for channeling of particles in accellerators / A. Mazzolari ... [et al.] -- New possibilities to facilitate collimation of both positively and negatively charged particle beams by crystals / V. Guidi, A. Mazzolari and V. V. Tikhomirov -- Increase of probability of particle capture into the channeling

  4. Ionic channels as electrostatic amplifiers of charge fluctuations

    CERN Document Server

    Luchinsky, D G; Kaufman, I; McClintock, P V E; Tindjong, R

    2006-01-01

    Electrostatic interaction between ions in an ionic channel and the charge fluctuations in the channel mouth are considered. It is shown that the charge fluctuations can be enhanced in the channels with low dielectric constant and result in strong modulation of the potential barrier at the selectivity site. The effect of charge fluctuational on transition probabilities in other molecular dynamical systems is briefly discussed.

  5. Irreversible inhibition of epithelial sodium channels by ultraviolet irradiation.

    OpenAIRE

    Cuthbert, A W; Fanestil, D. D.; Herrera, F. C.; Pryn, S. J.

    1982-01-01

    1 The effects of u.v. irradiation at 254 nm and 350 nm on sodium transport across frog skin epithelium have been investigated. 2 Irradiation at 254 nm but not at 350 nm produces a dose-dependent, functionally selective blockade of sodium transport. The effect is apparently due to the irreversible closure of apical sodium channels. 3 The amiloride-sensitive conductance was directly related to sodium transport as measured by short circuit current (SCC) both in normal and irradiated tissues, alt...

  6. Adsorption of Potassium and Sodium Ions by Variable Charge Soils

    Institute of Scientific and Technical Information of China (English)

    LIHONG-YAN; JIGUO-LIANG

    1992-01-01

    Adsorption of potassium and sodium ions by four typical variable charge soils of South China was studied.The results indicated that the variable charge soils saturated with H and Al showed a much higher preference for potassium ions relative to sodium ions,and this tendence could not be changed by such factors as the pH,the concentration of the cations,the dielectric constant of solvent,the accompanying anions and the iron oxide content etc.,suggesting that this difference in affinity is caused by the difference in the nature of the two cations.It was observed that a negative adsorption of sodium ions by latosol and lateritic red soil in a mixed system containing equal amount of potassium and sodium ions at low pH,which is caused by a competitive adsorption of potassium and sodium ions and repulsion of positive charge on the surfaces of soil particles for cations.The adsorption of potassium and sodium ions increased with the decreases in the dielectric constant of solvent and the iron oxide content.Sulfate affected the adsorption of potassium and sodium ions through changing the surface properties of the soils.

  7. The sodium-leak channel, NALCN, in health and disease

    OpenAIRE

    Maud eCochet-Bissuel; Philippe eLory; Arnaud eMonteil

    2014-01-01

    Ion channels are crucial components of cellular excitability and are involved in many neurological diseases. This review focuses on the sodium leak, G protein-coupled receptors (GPCRs)-activated NALCN channel that is predominantly expressed in neurons where it regulates the resting membrane potential and neuronal excitability. NALCN is part of a complex that includes not only GPCRs, but also UNC-79, UNC-80, NLF-1 and src family of Tyrosine kinases (SFKs). There is growing evidence that the NA...

  8. The sodium leak channel, NALCN, in health and disease

    OpenAIRE

    Cochet-Bissuel, Maud; Lory, Philippe; Monteil, Arnaud

    2014-01-01

    Ion channels are crucial components of cellular excitability and are involved in many neurological diseases. This review focuses on the sodium leak, G protein-coupled receptors (GPCRs)-activated NALCN channel that is predominantly expressed in neurons where it regulates the resting membrane potential and neuronal excitability. NALCN is part of a complex that includes not only GPCRs, but also UNC-79, UNC-80, NLF-1 and src family of Tyrosine kinases (SFKs). There is growing evidence that the NA...

  9. A sodium-channel mutation causes isolated cardiac conduction disease

    NARCIS (Netherlands)

    Tan, HL; Bink-Boelkens, MTE; Bezzina, CR; Viswanathan, PC; Beaufort-Krol, GCM; van Tintelen, PJ; van den Berg, MP; Wilde, AAM; Balser, [No Value

    2001-01-01

    Cardiac conduction disorders slow the heart rhythm and cause disability in millions of people worldwide. Inherited mutations in SCN5A, the gene encoding the human cardiac sodium (Na+) channel, have been associated with rapid heart rhythms that occur suddenly and are life-threatening(1-3); however, a

  10. Physiological regulation of epithelial sodium channel by proteolysis

    DEFF Research Database (Denmark)

    Svenningsen, Per; Friis, Ulla G; Bistrup, Claus;

    2011-01-01

    PURPOSE OF REVIEW: Activation of epithelial sodium channel (ENaC) by proteolysis appears to be relevant for day-to-day physiological regulation of channel activity in kidney and other epithelial tissues. Pathophysiogical, proteolytic activation of ENaC in kidney has been demonstrated in proteinuric...... disease. RECENT FINDINGS: A variation in sodium and potassium intake or plasma aldosterone changes the number of cleaved α and γ-ENaC subunits and is associated with changes in ENaC currents. The protease furin mediates intracellular cleavage, whereas the channel-activating protease prostasin (CAP-1...... is formed from filtered plasminogen via urokinase-type plasminogen activator. Plasmin activates ENaC directly at high concentrations and through prostasin at lower concentrations. SUMMARY: The discovery of serine protease-mediated activation of renal ENaC in physiological and pathophysiological conditions...

  11. Regulation of sodium channel function by bilayer elasticity

    DEFF Research Database (Denmark)

    Lundbaek, Jens A; Birn, Pia; Hansen, Anker J;

    2004-01-01

    kinetics of the protein conformational changes therefore will be regulated by the bilayer elasticity, which is determined by the lipid composition. This hydrophobic coupling mechanism has been studied extensively in gramicidin channels, where the channel-bilayer hydrophobic interactions link a...... "conformational" change (the monomerdimer transition) to an elastic bilayer deformation. Gramicidin channels thus are regulated by the lipid bilayer elastic properties (thickness, monolayer equilibrium curvature, and compression and bending moduli). To investigate whether this hydrophobic coupling mechanism could...... be a general mechanism regulating membrane protein function, we examined whether voltage-dependent skeletal-muscle sodium channels, expressed in HEK293 cells, are regulated by bilayer elasticity, as monitored using gramicidin A (gA) channels. Nonphysiological amphiphiles (beta...

  12. Energetics of discrete selectivity bands and mutation-induced transitions in the calcium-sodium ion channels family

    CERN Document Server

    Kaufman, I; Tindjong, R; McClintock, P V E; Eisenberg, R S

    2013-01-01

    We use Brownian dynamics simulations to study the permeation properties of a generic electrostatic model of a biological ion channel as a function of the fixed charge Q_f at its selectivity filter. We reconcile the recently-discovered discrete calcium conduction bands M0 (Q_f=1e), M1 (3e), M2 (5e) with the set of sodium conduction bands L0 (0.5-0.7e), L1 (1.5-2e) thereby obtaining a completed pattern of conduction and selectivity bands v Q_f for the sodium-calcium channels family. An increase of Q_f leads to an increase of calcium selectivity: L0 (sodium selective, non-blocking channel) -> M0 (non-selective channel) -> L1 (sodium selective channel with divalent block) -> M1 (calcium selective channel exhibiting the anomalous mole fraction effect). We create a consistent identification scheme where the L1 band is identified with the eukaryotic (DEKA) sodium channel, and L0 (speculatively) with the bacterial NaChBac channel. The scheme created is able to account for the experimentally observed mutation-induced ...

  13. Divergent sodium channel defects in familial hemiplegic migraine

    OpenAIRE

    Kahlig, Kristopher M.; Rhodes, Thomas H.; Pusch, Michael; Freilinger, Tobias; Pereira-Monteiro, José M.; Ferrari, Michel D; van den Maagdenberg, Arn M. J.M.; Dichgans, Martin; George, Alfred L.

    2008-01-01

    Familial hemiplegic migraine type 3 (FHM3) is a severe autosomal dominant migraine disorder caused by mutations in the voltage-gated sodium channel NaV1.1 encoded by SCN1A. We determined the functional consequences of three mutations linked to FHM3 (L263V, Q1489K, and L1649Q) in an effort to identify molecular defects that underlie this inherited migraine disorder. Only L263V and Q1489K generated quantifiable sodium currents when coexpressed in tsA201 cells with the human β1 and β2 accessory ...

  14. Voltage-gated sodium channels in taste bud cells

    Directory of Open Access Journals (Sweden)

    Williams Mark E

    2009-03-01

    Full Text Available Abstract Background Taste bud cells transmit information regarding the contents of food from taste receptors embedded in apical microvilli to gustatory nerve fibers innervating basolateral membranes. In particular, taste cells depolarize, activate voltage-gated sodium channels, and fire action potentials in response to tastants. Initial cell depolarization is attributable to sodium influx through TRPM5 in sweet, bitter, and umami cells and an undetermined cation influx through an ion channel in sour cells expressing PKD2L1, a candidate sour taste receptor. The molecular identity of the voltage-gated sodium channels that sense depolarizing signals and subsequently initiate action potentials coding taste information to gustatory nerve fibers is unknown. Results We describe the molecular and histological expression profiles of cation channels involved in electrical signal transmission from apical to basolateral membrane domains. TRPM5 was positioned immediately beneath tight junctions to receive calcium signals originating from sweet, bitter, and umami receptor activation, while PKD2L1 was positioned at the taste pore. Using mouse taste bud and lingual epithelial cells collected by laser capture microdissection, SCN2A, SCN3A, and SCN9A voltage-gated sodium channel transcripts were expressed in taste tissue. SCN2A, SCN3A, and SCN9A were expressed beneath tight junctions in subsets of taste cells. SCN3A and SCN9A were expressed in TRPM5 cells, while SCN2A was expressed in TRPM5 and PKD2L1 cells. HCN4, a gene previously implicated in sour taste, was expressed in PKD2L1 cells and localized to cell processes beneath the taste pore. Conclusion SCN2A, SCN3A and SCN9A voltage-gated sodium channels are positioned to sense initial depolarizing signals stemming from taste receptor activation and initiate taste cell action potentials. SCN2A, SCN3A and SCN9A gene products likely account for the tetrodotoxin-sensitive sodium currents in taste receptor cells.

  15. Electrokinetic inversion of ion screening charges in nano-channels

    CERN Document Server

    Zhu, Xin; Ni, Sheng; Zhang, Xingye; Liu, Yang

    2016-01-01

    This work studies a counter-intuitive but basic process of ionic screening in nano-fluidic channels. Numerical simulations and perturbation analysis reveal that, under significant electrokinetic transport, the ion screening charges can be locally inverted in the channels: their charge sign becomes the same as that of the channel surface charges. The process is identified to originate from the coupling of longitudinal transport and junction electrostatics. This finding may revise the common understanding of ionic screening in nano-channels and indicates that their ion selectivity can be locally changed by transport. Furthermore, the charge inversion process results in a body force torque on channel fluids, which is a possible mechanism for vortex generation in the channels.

  16. Shellfish Toxins Targeting Voltage-Gated Sodium Channels

    OpenAIRE

    Fan Zhang; Xunxun Xu; Tingting Li; Zhonghua Liu

    2013-01-01

    Voltage-gated sodium channels (VGSCs) play a central role in the generation and propagation of action potentials in excitable neurons and other cells and are targeted by commonly used local anesthetics, antiarrhythmics, and anticonvulsants. They are also common targets of neurotoxins including shellfish toxins. Shellfish toxins are a variety of toxic secondary metabolites produced by prokaryotic cyanobacteria and eukaryotic dinoflagellates in both marine and fresh water systems, which can acc...

  17. Voltage-dependent sodium channels in an invertebrate striated muscle.

    Science.gov (United States)

    Schwartz, L M; Stühmer, W

    1984-08-01

    Striated skeletal muscles from the planktonic arrowworm Sagitta elegans (phylum Chaetognatha) were voltage-clamped. The muscles displayed classical voltage-dependent sodium channels that (i) showed peak transient currents when the membrane was depolarized 90 millivolts from rest, (ii) opened rapidly with peak currents flowing within 0.4 milliseconds at 4 degrees C, (iii) showed voltage-dependent inactivation with 50 percent inactivation at +25 millivolts from rest, and (iv) were blocked by 500 nanomolar tetrodotoxin. PMID:6330898

  18. Role of the sixth transmembrane segment of domain IV of the cockroach sodium channel in the action of sodium channel-blocker insecticides

    OpenAIRE

    Silver, Kristopher S.; Nomura, Yoshiko; Salgado, Vincent L.; Dong, Ke

    2009-01-01

    Sodium channel-blocker insecticides (SCBIs), such as indoxacarb and metaflumizone, are a new class of insecticides with a mechanism of action different from those of other insecticides that target sodium channels. SCBIs block sodium channels in a manner similar to local anesthetics (LA) such as lidocaine. Several residues, particularly F1579 and Y1586, in the sixth transmembrane segment (S6) of domain IV (IV) of rat Nav1.4 sodium channels are required for the action of LAs and SCBIs and may f...

  19. Voltage-gated sodium channels: biophysics, pharmacology, and related channelopathies

    Directory of Open Access Journals (Sweden)

    Eleonora eSavio Galimberti

    2012-07-01

    Full Text Available Voltage-gated sodium channels (VGSC are multi-molecular protein complexes expressed in both excitable and non-excitable cells. They are primarily formed by a pore-forming multi-spanning integral membrane glycoprotein (α-subunit that can be associated with one or more regulatory β-subunits. The latter are single-span integral membrane proteins that modulate the sodium current (INa and can also function as cell-adhesion molecules (CAMs. In-vitro some of the cell-adhesive functions of the β-subunits may play important physiological roles independently of the α-subunits. Other endogenous regulatory proteins named channel partners or channel interacting proteins (ChiPs like caveolin-3 and calmodulin/calmodulin kinase II (CaMKII can also interact and modulate the expression and/or function of VGSC. In addition to their physiological roles in cell excitability and cell adhesion, VGSC are the site of action of toxins (like tetrodotoxin and saxitoxin, and pharmacologic agents (like antiarrhythmic drugs, local anesthetics, antiepileptic drugs, and newly developed analgesics. Mutations in genes that encode α- and/or β-subunits as well as the ChiPs can affect the structure and biophysical properties of VGSC, leading to the development of diseases termed sodium channelopathies. This review will outline the structure, function and biophysical properties of VGSC as well as their pharmacology and associated channelopathies and highlight some of the recent advances in this field

  20. Multiple Sodium Channel Variants in the Mosquito Culex quinquefasciatus

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    Lin He, Ting Li, Lee Zhang, Nannan Liu

    2012-01-01

    Full Text Available Voltage-gated sodium channels are the target sites of both DDT and pyrethroid insecticides. The importance of alternative splicing as a key mechanism governing the structural and functional diversity of sodium channels and the resulting development of insecticide and acaricide resistance is widely recognized, as shown by the extensive research on characterizing alternative splicing and variants of sodium channels in medically and agriculturally important insect species. Here we present the first comparative study of multiple variants of the sodium channel transcripts in the mosquito Culex quinquefasciatus. The variants were classified into two categories, CxNa-L and CxNa-S based on their distinguishing sequence sizes of ~6.5 kb and ~4.0 kb, respectively, and generated via major extensive alternative splicing with minor small deletions/ insertions in susceptible S-Lab, low resistant HAmCqG0, and highly resistant HAmCqG8 Culex strains. Four alternative Cx-Na-L splice variants were identified, including three full length variants with three optional exons (2, 5, and 21i and one with in-frame-stop codons. Large, multi-exon-alternative splices were identified in the CxNa-S category. All CxNa-S splicing variants in the S-Lab and HAmCqG0 strains contained in-frame stop codons, suggesting that any resulting proteins would be truncated. The ~1000 to ~3000-fold lower expression of these splice variants with stop codons compared with the CxNa-L splicing variants may support the lower importance of these variants in S-Lab and HAmCqG0. Interestingly, two alternative splicing variants of CxNa-S in HAmCqG8 included entire ORFs but lacked exons 5 to18 and these two variants had much higher expression levels in HAmCqG8 than in S-Lab and HAmCqG0. These results provide a functional basis for further characterizing how alternative splicing of a voltage-gated sodium channel contributes to diversity in neuronal signaling in mosquitoes in response to pyrethroids, and

  1. Voltage-Gated Sodium Channels: Mechanistic Insights From Atomistic Molecular Dynamics Simulations.

    Science.gov (United States)

    Oakes, V; Furini, S; Domene, C

    2016-01-01

    The permeation of ions and other molecules across biological membranes is an inherent requirement of all cellular organisms. Ion channels, in particular, are responsible for the conduction of charged species, hence modulating the propagation of electrical signals. Despite the universal physiological implications of this property, the molecular functioning of ion channels remains ambiguous. The combination of atomistic structural data with computational methodologies, such as molecular dynamics (MD) simulations, is now considered routine to investigate structure-function relationships in biological systems. A fuller understanding of conduction, selectivity, and gating, therefore, is steadily emerging due to the applicability of these techniques to ion channels. However, because their structure is known at atomic resolution, studies have consistently been biased toward K(+) channels, thus the molecular determinants of ionic selectivity, activation, and drug blockage in Na(+) channels are often overlooked. The recent increase of available crystallographic data has eminently encouraged the investigation of voltage-gated sodium (NaV) channels via computational methods. Here, we present an overview of simulation studies that have contributed to our understanding of key principles that underlie ionic conduction and selectivity in Na(+) channels, in comparison to the K(+) channel analogs. PMID:27586285

  2. Neurotoxins and Their Binding Areas on Voltage-Gated Sodium Channels

    OpenAIRE

    Stevens, Marijke; Peigneur, Steve; Tytgat, Jan

    2011-01-01

    Voltage-gated sodium channels (VGSCs) are large transmembrane proteins that conduct sodium ions across the membrane and by doing so they generate signals of communication between many kinds of tissues. They are responsible for the generation and propagation of action potentials in excitable cells, in close collaboration with other channels like potassium channels. Therefore, genetic defects in sodium channel genes can cause a wide variety of diseases, generally called “channelopathies.” The f...

  3. Neurotoxins and their binding areas on voltage-gated sodium channels

    OpenAIRE

    Marijke eStevens; Steve ePeigneur; Jan eTytgat

    2011-01-01

    Voltage-gated Sodium Channels (VGSCs) are large transmembrane proteins that conduct sodium ions across the membrane and by doing so they generate signals of communication between many kinds of tissues. They are responsible for the generation and propagation of action potentials in excitable cells, in close collaboration with other channels like potassium channels. Genetic defects in sodium channel genes therefore can cause a wide variety of diseases, generally called ‘channelopathies’.The f...

  4. Docking Studies of Phthalimide Pharmacophore as a Sodium Channel Blocker

    Directory of Open Access Journals (Sweden)

    Maryam Iman

    2013-09-01

    Full Text Available   Objective(s: Recently, phthalimide derivatives were designed based on ameltolide and thalidomide as they possess a similar degree of anticonvulsant potency due to their phenytoin-like profile. The ability of phthalimide pharmacophore to interact with neuronal voltage-dependent sodium channels was studied in the batrachotoxin affinity assay. Therefore, in the present study, a series of 19 compounds of phthalimide pharmacophore possessing a variety of substituents (NO2, NH2 , Me, Cl, COOH, MeO at 2-, 3-, and 4- position of the N-phenyl ring and N-(3-amino-2-methylphenyl succinimide, were subjected to docking studies in order to inhibit voltage-gated sodium channels.   Materials and Methods : Chemical structures of all compounds were designed using HYPERCHEM program and Conformational studies were performed through semi-empirical molecular orbital calculations method followed by PM3 force field. Total energy gradient calculated as a root mean square (RMS value, until the RMS gradient was 0.01 kcal mol-1. Among all energy minima conformers, the global minimum of compounds was used in docking calculations. Using a model of the open pore of Na channels, docking study was performed by AUTODOCK4.2 program. Results : Docking studies have revealed that these types of ligands interacted mainly with II-S6 residues of NaV1.2 through making hydrogen bonds and have additional hydrophobic interactions with domain I, II, III and IV in the channel's inner pore. Conclusion   : These computational studies have displayed that these compounds are capable of inhibiting Na channel, efficiently.

  5. Marine Toxins That Target Voltage-gated Sodium Channels

    Directory of Open Access Journals (Sweden)

    Robert J. French

    2006-04-01

    Full Text Available Abstract: Eukaryotic, voltage-gated sodium (NaV channels are large membrane proteins which underlie generation and propagation of rapid electrical signals in nerve, muscle and heart. Nine different NaV receptor sites, for natural ligands and/or drugs, have been identified, based on functional analyses and site-directed mutagenesis. In the marine ecosystem, numerous toxins have evolved to disrupt NaV channel function, either by inhibition of current flow through the channels, or by modifying the activation and inactivation gating processes by which the channels open and close. These toxins function in their native environment as offensive or defensive weapons in prey capture or deterrence of predators. In composition, they range from organic molecules of varying size and complexity to peptides consisting of ~10-70 amino acids. We review the variety of known NaV-targeted marine toxins, outlining, where known, their sites of interaction with the channel protein and their functional effects. In a number of cases, these natural ligands have the potential applications as drugs in clinical settings, or as models for drug development.

  6. Adaptive evolution of the vertebrate skeletal muscle sodium channel

    Directory of Open Access Journals (Sweden)

    Jian Lu

    2011-01-01

    Full Text Available Tetrodotoxin (TTX is a highly potent neurotoxin that blocks the action potential by selectively binding to voltage-gated sodium channels (Na v. The skeletal muscle Na v (Na v1.4 channels in most pufferfish species and certain North American garter snakes are resistant to TTX, whereas in most mammals they are TTX-sensitive. It still remains unclear as to whether the difference in this sensitivity among the various vertebrate species can be associated with adaptive evolution. In this study, we investigated the adaptive evolution of the vertebrate Na v1.4 channels. By means of the CODEML program of the PAML 4.3 package, the lineages of both garter snakes and pufferfishes were denoted to be under positive selection. The positively selected sites identified in the p-loop regions indicated their involvement in Na v1.4 channel sensitivity to TTX. Most of these sites were located in the intracellular regions of the Na v1.4 channel, thereby implying the possible association of these regions with the regulation of voltage-sensor movement.

  7. Thermally stratified sodium channel flow: turbulence and modeling

    International Nuclear Information System (INIS)

    Numerical simulation of sodium stratification in open channel flow has been studied with Computational Fluid Dynamics (CFD) employing an Algebraic Heat Flux Model (AHFM) closure for the turbulent heat flux. The results are validated against experimental data and the AHFM is compared with the simplified Reynolds analogy employing a constant turbulent Pr number. Influence of buoyancy on turbulence created in the mixing layer has been evaluated and its influence on the momentum and energy transport in the vertical direction assessed. It has been found that the choice of turbulent heat flux model influences the achieved results for temperature and velocity field which might affect the flow developing and persistence of stratification in the channel. Moreover both experiment and validation show the possibility of creation of a strong stratification also for low Pr number fluids, warning the stratification problem as an existing phenomenon likely to occur in liquid metal nuclear power plants. (author)

  8. A sodium channel mutation identified in Aedes aegypti selectively reduces cockroach sodium channel sensitivity to type I, but not type II pyrethroids.

    Science.gov (United States)

    Hu, Zhaonong; Du, Yuzhe; Nomura, Yoshiko; Dong, Ke

    2011-01-01

    Voltage-gated sodium channels are the primary target of pyrethroid insecticides. Numerous point mutations in sodium channel genes have been identified in pyrethroid-resistant insect species, and many have been confirmed to reduce or abolish sensitivity of channels expressed in Xenopus oocytes to pyrethroids. Recently, several novel mutations were reported in sodium channel genes of pyrethroid-resistant Aedes mosquito populations. One of the mutations is a phenylalanine (F) to cysteine (C) change in segment 6 of domain III (IIIS6) of the Aedes mosquito sodium channel. Curiously, a previous study showed that alanine substitution of this F did not alter the action of deltamethrin, a type II pyrethroid, on a cockroach sodium channel. In this study, we changed this F to C in a pyrethroid-sensitive cockroach sodium channel and examined mutant channel sensitivity to permethrin as well as five other type I or type II pyrethroids in Xenopus oocytes. Interestingly, the F to C mutation drastically reduced channel sensitivity to three type I pyrethroids, permethrin, NRDC 157 (a deltamethrin analogue lacking the α-cyano group) and bioresemthrin, but not to three type II pyrethroids, cypermethrin, deltamethrin and cyhalothrin. These results confirm the involvement of the F to C mutation in permethrin resistance, and raise the possibility that rotation of type I and type II pyrethroids might be considered in the control of insect pest populations where this particular mutation is present.

  9. Controlling epithelial sodium channels with light using photoswitchable amilorides

    Science.gov (United States)

    Schönberger, Matthias; Althaus, Mike; Fronius, Martin; Clauss, Wolfgang; Trauner, Dirk

    2014-08-01

    Amiloride is a widely used diuretic that blocks epithelial sodium channels (ENaCs). These heterotrimeric transmembrane proteins, assembled from β, γ and α or δ subunits, effectively control water transport across epithelia and sodium influx into non-epithelial cells. The functional role of δβγENaC in various organs, including the human brain, is still poorly understood and no pharmacological tools are available for the functional differentiation between α- and δ-containing ENaCs. Here we report several photoswitchable versions of amiloride. One compound, termed PA1, enables the optical control of ENaC channels, in particular the δβγ isoform, by switching between blue and green light, or by turning on and off blue light. PA1 was used to modify functionally δβγENaC in amphibian and mammalian cells. We also show that PA1 can be used to differentiate between δβγENaC and αβγENaC in a model for the human lung epithelium.

  10. The sodium channel as a target for local anesthetic drugs

    Directory of Open Access Journals (Sweden)

    Harry A Fozzard

    2011-11-01

    Full Text Available Na channels are the source of excitatory currents for the nervous system and muscle. They are the target for a class of drugs called local anesthetics (LA, which have been used for local and regional anesthesia and for excitatory dysfunction problems such as epilepsy and cardiac arrhythmia. LA drugs are prototypes for new analgesic drugs. The LA drug binding site has been localized to the inner pore of the channel, where drugs interact mainly with a phenylalanine in domain IV S6. Drug affinity is both voltage- and use-dependent. Voltage-dependency is the result of changes in the conformation of the inner pore during channel activation and opening, allowing high energy interaction of drugs with the phenylalanine. LA drugs also reduce the gating current of Na channels, which represents the movement of charged residues in the voltage sensors. Specifically, drug binding to phenylalanine locks the domain III S4 in its outward (activated position, and slows recovery of the domain IV S4. Although strongly affecting gating, LA drugs almost certainly also block by steric occlusion of the pore. Molecular definition of the binding and blocking interactions may help in new drug development.

  11. Potential Roles of Amiloride-Sensitive Sodium Channels in Cancer Development

    OpenAIRE

    Xu, Siguang; Liu, Cui; Ma, Yana; Ji, Hong-Long; Li, Xiumin

    2016-01-01

    The ENaC/degenerin ion channel superfamily includes the amiloride-sensitive epithelial sodium channel (ENaC) and acid sensitive ionic channel (ASIC). ENaC is a multimeric ion channel formed by heteromultimeric membrane glycoproteins, which participate in a multitude of biological processes by mediating the transport of sodium (Na+) across epithelial tissues such as the kidney, lungs, bladder, and gut. Aberrant ENaC functions contribute to several human disease states including pseudohypoaldos...

  12. Shellfish Toxins Targeting Voltage-Gated Sodium Channels

    Directory of Open Access Journals (Sweden)

    Fan Zhang

    2013-11-01

    Full Text Available Voltage-gated sodium channels (VGSCs play a central role in the generation and propagation of action potentials in excitable neurons and other cells and are targeted by commonly used local anesthetics, antiarrhythmics, and anticonvulsants. They are also common targets of neurotoxins including shellfish toxins. Shellfish toxins are a variety of toxic secondary metabolites produced by prokaryotic cyanobacteria and eukaryotic dinoflagellates in both marine and fresh water systems, which can accumulate in marine animals via the food chain. Consumption of shellfish toxin-contaminated seafood may result in potentially fatal human shellfish poisoning. This article provides an overview of the structure, bioactivity, and pharmacology of shellfish toxins that act on VGSCs, along with a brief discussion on their pharmaceutical potential for pain management.

  13. Plasmin in nephrotic urine activates the epithelial sodium channel

    DEFF Research Database (Denmark)

    Svenningsen, Per; Bistrup, Claus; Friis, Ulla G;

    2008-01-01

    Proteinuria and increased renal reabsorption of NaCl characterize the nephrotic syndrome. Here, we show that protein-rich urine from nephrotic rats and from patients with nephrotic syndrome activate the epithelial sodium channel (ENaC) in cultured M-1 mouse collecting duct cells and in Xenopus...... laevis oocytes heterologously expressing ENaC. The activation depended on urinary serine protease activity. We identified plasmin as a urinary serine protease by matrix-assisted laser desorption/ionization time of-flight mass spectrometry. Purified plasmin activated ENaC currents, and inhibitors...... of plasmin abolished urinary protease activity and the ability to activate ENaC. In nephrotic syndrome, tubular urokinase-type plasminogen activator likely converts filtered plasminogen to plasmin. Consistent with this, the combined application of urokinase-type plasminogen activator and plasminogen...

  14. Biophysical Adaptations of Prokaryotic Voltage-Gated Sodium Channels.

    Science.gov (United States)

    Vien, T N; DeCaen, P G

    2016-01-01

    This chapter describes the adaptive features found in voltage-gated sodium channels (NaVs) of prokaryotes and eukaryotes. These two families are distinct, having diverged early in evolutionary history but maintain a surprising degree of convergence in function. While prokaryotic NaVs are required for growth and motility, eukaryotic NaVs selectively conduct fast electrical currents for short- and long-range signaling across cell membranes in mammalian organs. Current interest in prokaryotic NaVs is stoked by their resolved high-resolution structures and functional features which are reminiscent of eukaryotic NaVs. In this chapter, comparisons between eukaryotic and prokaryotic NaVs are made to highlight the shared and unique aspects of ion selectivity, voltage sensitivity, and pharmacology. Examples of prokaryotic and eukaryotic NaV convergent evolution will be discussed within the context of their structural features. PMID:27586280

  15. Blood pressure and amiloride-sensitive sodium channels in vascular and renal cells.

    Science.gov (United States)

    Warnock, David G; Kusche-Vihrog, Kristina; Tarjus, Antoine; Sheng, Shaohu; Oberleithner, Hans; Kleyman, Thomas R; Jaisser, Frederic

    2014-03-01

    Sodium transport in the distal nephron is mediated by epithelial sodium channel activity. Proteolytic processing of external domains and inhibition with increased sodium concentrations are important regulatory features of epithelial sodium channel complexes expressed in the distal nephron. By contrast, sodium channels expressed in the vascular system are activated by increased external sodium concentrations, which results in changes in the mechanical properties and function of endothelial cells. Mechanosensitivity and shear stress affect both epithelial and vascular sodium channel activity. Guyton's hypothesis stated that blood pressure control is critically dependent on vascular tone and fluid handling by the kidney. The synergistic effects, and complementary regulation, of the epithelial and vascular systems are consistent with the Guytonian model of volume and blood pressure regulation, and probably reflect sequential evolution of the two systems. The integration of vascular tone, renal perfusion and regulation of renal sodium reabsorption is the central underpinning of the Guytonian model. In this Review, we focus on the expression and regulation of sodium channels, and we outline the emerging evidence that describes the central role of amiloride-sensitive sodium channels in the efferent (vascular) and afferent (epithelial) arms of this homeostatic system.

  16. The sodium-leak channel, NALCN, in health and disease

    Directory of Open Access Journals (Sweden)

    Maud eCochet-Bissuel

    2014-05-01

    Full Text Available Ion channels are crucial components of cellular excitability and are involved in many neurological diseases. This review focuses on the sodium leak, G protein-coupled receptors (GPCRs-activated NALCN channel that is predominantly expressed in neurons where it regulates the resting membrane potential and neuronal excitability. NALCN is part of a complex that includes not only GPCRs, but also UNC-79, UNC-80, NLF-1 and src family of Tyrosine kinases (SFKs. There is growing evidence that the NALCN channelosome critically regulates its ion conduction. Both in mammals and invertebrates, animal models revealed an involvement in many processes such as locomotor behaviours, sensitivity to volatile anesthetics, and respiratory rhythms. There is also evidence that alteration in this NALCN channelosome can cause a wide variety of diseases. Indeed, mutations in the NALCN gene were identified in Infantile Neuroaxonal Dystrophy (INAD patients, as well as in patients with an Autosomal Recessive Syndrome with severe hypotonia, speech impairment, and cognitive delay. Deletions in NALCN gene were also reported in diseases such as 13q syndrome. In addition, genes encoding NALCN, NLF- 1, UNC-79 and UNC-80 proteins may be susceptibility loci for several diseases including bipolar disorder, schizophrenia, Alzheimer’s disease, autism, epilepsy, alcoholism, cardiac diseases and cancer. Although the physiological role of the NALCN channelosome is poorly understood, its involvement in human diseases should foster interest for drug development in the near future. Towards this goal, we review here the current knowledge on the NALCN channelosome in physiology and diseases.

  17. Cation gating and selectivity in a purified, reconstituted, voltage-dependent sodium channel

    International Nuclear Information System (INIS)

    In excitable membranes, the voltage-dependent sodium channel controls the primary membrane conductance change necessary for the generation of an action potential. Over the past four decades, the time- and voltage-dependent sodium currents gated by this channel have been thoroughly documented with increasingly sophisticated voltage-clamp techniques. Recent advances in the biochemistry of membrane proteins have led to the solubilization and purification of this channel protein from nerve (6) and from muscle (4) or muscle-derived (1) membranes, and have provided an approach to the correlation of the channel's molecular structure with its functional properties. Each of these sodium channel preparations appears to contain a large glycoprotein either as its sole component (2) or in association with several small subunits (6, 3). Evidence that these purified proteins represent the excitable membrane sodium channel is presented. 8 refs., 1 fig., 1 tab

  18. Action of the pyrethroid insecticide cypermethrin on rat brain IIa sodium channels expressed in xenopus oocytes.

    Science.gov (United States)

    Smith, T J; Soderlund, D M

    1998-12-01

    Pyrethroid insecticides bind to a unique site on voltage-dependent sodium channels and prolong sodium currents, leading to repetitive bursts of action potentials or use-dependent nerve block. To further characterize the site and mode of action of pyrethroids on sodium channels, we injected synthetic mRNA encoding the rat brain IIa sodium channel alpha subunit, either alone or in combination with synthetic mRNA encoding the rat sodium channel beta1 subunit, into oocytes of the frog Xenopus laevis and assessed the actions of the pyrethroid insecticide [1R,cis,alphaS]-cypermethrin on expressed sodium currents by two-electrode voltage clamp. In oocytes expressing only the rat brain IIa alpha subunit, cypermethrin produced a slowly-decaying sodium tail current following a depolarizing pulse. In parallel experiments using oocytes expressing the rat brain IIa alpha subunit in combination with the rat beta1 subunit, cypermethrin produced qualitatively similar tail currents following a depolarizing pulse and also induced a sustained component of the sodium current measured during a step depolarization of the oocyte membrane. The voltage dependence of activation and steady-state inactivation of the cypermethrin-dependent sustained current were identical to those of the peak transient sodium current measured in the absence of cypermethrin. Concentration-response curves obtained using normalized tail current amplitude as an index of the extent of sodium channel modification by cypermethrin revealed that coexpression of the rat brain IIa alpha subunit with the rat beta1 subunit increased the apparent affinity of the sodium channel binding site for cypermethrin by more than 20-fold. These results confirm that the pyrethroid binding site is intrinsic to the sodium channel alpha subunit and demonstrate that coexpression of the rat brain IIa alpha subunit with the rat beta1 subunit alters the apparent affinity of this site for pyrethroids.

  19. Could a defective epithelial sodium channel lead to bronchiectasis

    Directory of Open Access Journals (Sweden)

    Hubert Dominique

    2008-05-01

    Full Text Available Abstract Background Bronchiectasis is defined as a permanent dilation of the airways arising from chronic bronchial inflammation/infection. In 50% of cases, no etiology can be identified. Recently, the role of the epithelial sodium channel ENaC has been pointed out in the pathophysiology of cystic fibrosis, a disease due to mutations in the CFTR gene and causing bronchiectasis in the airways. Moreover, it was found that transgenic mice overexpressing ENaCβ present cystic fibrosis-like lung disease symptoms. Our aim was to evaluate if a defective ENaC protein could be involved in the development of bronchiectasis. Methods We extensively analysed ENaCβ and γ genes in 55 patients with idiopathic bronchiectasis and without two mutations in the coding regions of CFTR. Thirty-eight patients presented functional abnormalities suggesting impaired sodium transport (abnormal sweat chloride concentration or nasal potential difference measurement, and 17 had no such evidence. Results Sequencing of the exons and flanking introns of the ENaCβ and γ gene identified five different amino-acid changes (p.Ser82Cys, p.Pro369Thr, p.Asn288Ser in ENaCβ ; and p.Gly183Ser, p.Glu197Lys in ENaCγ in heterozygous state in 8 patients. The p.Ser82Cys amino-acid change was found in 3 unrelated patients who were also heterozygous for a CFTR mutation or variant (1 p.F508del, 1 IVS8-5T, and 1 IVS8-5T:1716G>A (p.E528E. The other mutations were found in patients without CFTR mutation, the p.Glu197Lys mutation in 2 patients and the other variants in single patients. Among the 8 patients bearing an ENaC mutation, 5 had functional abnormalities suggesting impaired sodium transport. Conclusion Our results suggest that several variants in ENaCβ and γ genes might be deleterious for ENaC function and lead to bronchiectasis, especially in patients who are trans-heterozygotes for ENaCβ/CFTR mutations or variants.

  20. Difference of Sodium Currents between Pediatric and Adult Human Atrial Myocytes: Evidence for Developmental Changes of Sodium Channels

    Directory of Open Access Journals (Sweden)

    Benzhi Cai, Xiaoqin Mu, Dongmei Gong, Shulin Jiang, Jianping Li, Qingxin Meng, Yunlong Bai, Yanju Liu, Xinyue Wang, Xueying Tan, Baofeng Yang, Yanjie Lu

    2011-01-01

    Full Text Available Voltage-gated calcium currents and potassium currents were shown to undergo developmental changes in postnatal human and animal cardiomocytes. However, so far, there is no evidence whether sodium currents also presented the developmental changes in postnatal human atrial cells. The aim of this study was to observe age-related changes of sodium currents between pediatric and adult atrial myocytes. Human atrial myocytes were acutely isolated and the whole-cell patch clamp technique was used to record sodium currents isolated from pediatric and adult atrial cardiomocytes. The peak amplitude of sodium currents recorded in adult atrial cells was significantly larger than that in pediatric atrial myocytes. However, there was no significant difference of the activation voltage for peak sodium currents between two kinds of atrial myocytes. The time constants for the activation and inactivation of sodium currents were smaller in adult atria than pediatric atria. The further study revealed that the voltage-dependent inactivation of sodium currents were more slow in adult atrial cardiomyocytes than pediatric atrial cells. A significant difference was also observed in the recovery process of sodium channel from inactivation. In summary, a few significant differences were demonstrated in sodium currents characteristics between pediatric and adult atrial myocytes, which indicates that sodium currents in human atria also undergo developmental changes.

  1. Lysine and the Na+/K+ Selectivity in Mammalian Voltage-Gated Sodium Channels.

    Science.gov (United States)

    Li, Yang; Liu, Huihui; Xia, Mengdie; Gong, Haipeng

    2016-01-01

    Voltage-gated sodium (Nav) channels are critical in the generation and transmission of neuronal signals in mammals. The crystal structures of several prokaryotic Nav channels determined in recent years inspire the mechanistic studies on their selection upon the permeable cations (especially between Na+ and K+ ions), a property that is proposed to be mainly determined by residues in the selectivity filter. However, the mechanism of cation selection in mammalian Nav channels lacks direct explanation at atomic level due to the difference in amino acid sequences between mammalian and prokaryotic Nav homologues, especially at the constriction site where the DEKA motif has been identified to determine the Na+/K+ selectivity in mammalian Nav channels but is completely absent in the prokaryotic counterparts. Among the DEKA residues, Lys is of the most importance since its mutation to Arg abolishes the Na+/K+ selectivity. In this work, we modeled the pore domain of mammalian Nav channels by mutating the four residues at the constriction site of a prokaryotic Nav channel (NavRh) to DEKA, and then mechanistically investigated the contribution of Lys in cation selection using molecular dynamics simulations. The DERA mutant was generated as a comparison to understand the loss of ion selectivity caused by the K-to-R mutation. Simulations and free energy calculations on the mutants indicate that Lys facilitates Na+/K+ selection by electrostatically repelling the cation to a highly Na+-selective location sandwiched by the carboxylate groups of Asp and Glu at the constriction site. In contrast, the electrostatic repulsion is substantially weakened when Lys is mutated to Arg, because of two intrinsic properties of the Arg side chain: the planar geometric design and the sparse charge distribution of the guanidine group. PMID:27584582

  2. Native pyroglutamation of huwentoxin-IV: a post-translational modification that increases the trapping ability to the sodium channel.

    Directory of Open Access Journals (Sweden)

    Mingqiang Rong

    Full Text Available Huwentoxin-IV (HWTX-IV, a tetrodotoxin-sensitive (TTX-s sodium channel antagonist, is found in the venom of the Chinese spider Ornithoctonus huwena. A naturally modified HWTX-IV (mHWTX-IV, having a molecular mass 18 Da lower than HWTX-IV, has also been isolated from the venom of the same spider. By a combination of enzymatic fragmentation and MS/MS de novo sequencing, mHWTX-IV has been shown to have the same amino acid sequence as that of HWTX-IV, except that the N-terminal glutamic acid replaced by pyroglutamic acid. mHWTX-IV inhibited tetrodotoxin-sensitive voltage-gated sodium channels of dorsal root ganglion neurons with an IC50 nearly equal to native HWTX-IV. mHWTX-IV showed the same activation and inactivation kinetics seen for native HWTX-IV. In contrast with HWTX-IV, which dissociates at moderate voltage depolarization voltages (+50 mV, 180000 ms, mHWTX-IV inhibition of TTX-sensitive sodium channels is not reversed by strong depolarization voltages (+200 mV, 500 ms. Recovery of Nav1.7current was voltage-dependent and was induced by extreme depolarization in the presence of HWTX-IV, but no obvious current was elicited after application of mHWTX-IV. Our data indicate that the N-terminal modification of HWTX-IV gives the peptide toxin a greater ability to trap the voltage sensor in the sodium channel. Loss of a negative charge, caused by cyclization at the N-terminus, is a possible reason why the modified toxin binds much stronger. To our knowledge, this is the first report of a pyroglutamic acid residue in a spider toxin; this modification seems to increase the trapping ability of the voltage sensor in the sodium channel.

  3. Sodium channel gene expression in mosquitoes, Aedes albopictus (S.)

    Institute of Scientific and Technical Information of China (English)

    NANNAN LIU; QIANG XU; LEE ZHANG

    2006-01-01

    A mosquito strain of Aerdes albopictus,HAmAalG0,from Huntsville,Alabama,USA,showed a normal susceptibility and low tolerance to permethrin and resmethrin (pyrethroid insecticides) compared to a susceptible Ikaken strain,even though these pyrethroid insecticides have been used in the field for a long period of time in Alabama.Recently,we treated HAmAalG0 in the laboratory with permethrin for five generations and detected no significant change in the level of resistance to permethrin in the selected mosquitoes,HAmAalG5,compared with the parental strain HAmAalG0. We then examined the allelic expression at the L-to-F kdr site of the sodium channel gene in the Aedes mosquitoes to address our hypothesis that the L-to-F kdr mutation was not present in HAmAalG0 and HAmAalG5 mosquitoes. We found that every tested individual in Ikaken,HAmAalG0,and HAmAalG5 populations expressed a codon of CTA at the L-to-F kdr site encoding Leu,strongly corresponding to their susceptibility to insecticides.

  4. Cloning and molecular characterization of a putative voltage-gated sodium channel gene in the crayfish.

    Science.gov (United States)

    Coskun, Cagil; Purali, Nuhan

    2016-06-01

    Voltage-gated sodium channel genes and associated proteins have been cloned and studied in many mammalian and invertebrate species. However, there is no data available about the sodium channel gene(s) in the crayfish, although the animal has frequently been used as a model to investigate various aspects of neural cellular and circuit function. In the present work, by using RNA extracts from crayfish abdominal ganglia samples, the complete open reading frame of a putative sodium channel gene has firstly been cloned and molecular properties of the associated peptide have been analyzed. The open reading frame of the gene has a length of 5793 bp that encodes for the synthesis of a peptide, with 1930 amino acids, that is 82% similar to the α-peptide of a sodium channel in a neighboring species, Cancer borealis. The transmembrane topology analysis of the crayfish peptide indicated a pattern of four folding domains with several transmembrane segments, as observed in other known voltage-gated sodium channels. Upon analysis of the obtained sequence, functional regions of the putative sodium channel responsible for the selectivity filter, inactivation gate, voltage sensor, and phosphorylation have been predicted. The expression level of the putative sodium channel gene, as defined by a qPCR method, was measured and found to be the highest in nervous tissue. PMID:27032955

  5. The Sodium-Activated Potassium Channel Slack Is Required for Optimal Cognitive Flexibility in Mice

    Science.gov (United States)

    Bausch, Anne E.; Dieter, Rebekka; Nann, Yvette; Hausmann, Mario; Meyerdierks, Nora; Kaczmarek, Leonard K.; Ruth, Peter; Lukowski, Robert

    2015-01-01

    "Kcnt1" encoded sodium-activated potassium channels (Slack channels) are highly expressed throughout the brain where they modulate the firing patterns and general excitability of many types of neurons. Increasing evidence suggests that Slack channels may be important for higher brain functions such as cognition and normal intellectual…

  6. Design of a Nested Eight-Channel Sodium and Four-Channel Proton Coil for 7 Tesla Knee Imaging

    OpenAIRE

    Brown, Ryan; Madelin, Guillaume; Lattanzi, Riccardo; Chang, Gregory; Regatte, Ravinder R.; Sodickson, Daniel K.; Wiggins, Graham C.

    2012-01-01

    The critical design aim for a dual-tuned sodium/proton coil is to maximize sodium sensitivity and transmit field (B1+) homogeneity while simultaneously providing adequate proton sensitivity and homogeneity. While most dual-frequency coils utilize lossy high-impedance trap circuits or PIN diodes to allow dual-resonance, we explored a nested-coil design for sodium/proton knee imaging at 7T. A stand-alone eight-channel sodium receive array was implemented without standard dual-resonance circuitr...

  7. A technique to improve crystal channeling efficiency of charged particles

    CERN Document Server

    Tikhomirov, V V

    2007-01-01

    It is shown that a narrow plane cut near the crystal surface considerably increases the probability of capture into the stable channeling motion of positively charged particles entering a crystal at angles smaller than a quarter of the critical channeling angle with respect to the crystal planes. At smallest incidence angles the capture probability reaches 99 percent. A pair of crystals bent in orthogonal planes and provided with the cuts allows to reach a 99.9 percent efficiency of single-pass deflection of a proton beam with an ultra small divergence. Conditions necessary for efficient single-pass deflection of protons from the LHC beam halo are also discussed.

  8. Pinostrobin from Cajanus cajan (L.) Millsp. inhibits sodium channel-activated depolarization of mouse brain synaptoneurosomes.

    Science.gov (United States)

    Nicholson, Russell A; David, Laurence S; Pan, Rui Le; Liu, Xin Min

    2010-10-01

    This investigation focuses on the in vitro neuroactive properties of pinostrobin, a substituted flavanone from Cajanus cajan (L.) Millsp. of the Fabaceae family. We demonstrate that pinostrobin inhibits voltage-gated sodium channels of mammalian brain (IC(50)=23 µM) based on the ability of this substance to suppress the depolarizing effects of the sodium channel-selective activator veratridine in a synaptoneurosomal preparation from mouse brain. The resting membrane potential of synaptoneurosomes was unaffected by pinostrobin. The pharmacological profile of pinostrobin resembles that of depressant drugs that block sodium channels. PMID:20472040

  9. Discovery of potent furan piperazine sodium channel blockers for treatment of neuropathic pain.

    Science.gov (United States)

    Drizin, Irene; Gregg, Robert J; Scanio, Marc J C; Shi, Lei; Gross, Michael F; Atkinson, Robert N; Thomas, James B; Johnson, Matthew S; Carroll, William A; Marron, Brian E; Chapman, Mark L; Liu, Dong; Krambis, Michael J; Shieh, Char-Chang; Zhang, XuFeng; Hernandez, Gricelda; Gauvin, Donna M; Mikusa, Joseph P; Zhu, Chang Z; Joshi, Shailen; Honore, Prisca; Marsh, Kennan C; Roeloffs, Rosemarie; Werness, Stephen; Krafte, Douglas S; Jarvis, Michael F; Faltynek, Connie R; Kort, Michael E

    2008-06-15

    The synthesis and pharmacological characterization of a novel furan-based class of voltage-gated sodium channel blockers is reported. Compounds were evaluated for their ability to block the tetrodotoxin-resistant sodium channel Na(v)1.8 (PN3) as well as the Na(v)1.2 and Na(v)1.5 subtypes. Benchmark compounds from this series possessed enhanced potency, oral bioavailability, and robust efficacy in a rodent model of neuropathic pain, together with improved CNS and cardiovascular safety profiles compared to the clinically used sodium channel blockers mexiletine and lamotrigine. PMID:18501613

  10. A Unified Channel Charges Expression for Analytic MOSFET Modeling

    OpenAIRE

    Hugues Murray; Patrick Martin

    2012-01-01

    Based on a 1D Poissons equation resolution, we present an analytic model of inversion charges allowing calculation of the drain current and transconductance in the Metal Oxide Semiconductor Field Effect Transistor. The drain current and transconductance are described by analytical functions including mobility corrections and short channel effects (CLM, DIBL). The comparison with the Pao-Sah integral shows excellent accuracy of the model in all inversion modes from strong to weak inversion in ...

  11. Hapalindoles from the cyanobacterium fischerella: potential sodium channel modulators.

    Science.gov (United States)

    Cagide, Eva; Becher, Paul G; Louzao, M Carmen; Espiña, Begoña; Vieytes, Mercedes R; Jüttner, Friedrich; Botana, Luis M

    2014-10-20

    Hapalindoles make up a large group of bioactive metabolites of the cyanobacterial order Stigonematales. 12-epi-Hapalindole E isonitrile, 12-epi-hapalindole C isonitrile, 12-epi-hapalindole J isonitrile, and hapalindole L from Fischerella are acutely toxic for insect larvae; however, the biochemical targets responsible for the biological activities of hapalindoles are not understood. We describe here the electron impact mass spectra of these four hapalindole congeners; their structures were confirmed by nuclear magnetic resonance spectroscopy. In combination with the presented mass spectra of (15)N-labeled species and their retention times on a gas chromatography capillary column, a rapid and reliable determination should be possible in future research. The bioactivity of these hapalindoles was tested on mammalian cells focusing on their effects in the BE(2)-M17 excitable human neuroblastoma cell line. The fluorescent dye Alamar Blue was applied to monitor cytotoxicity, fura-2 to evaluate changes in the cytosolic calcium concentrations, and bis-oxonol to detect effects on membrane potential. Data showed that the hapalindoles did not affect cell viability of the neuroblastoma cells, even when they were incubated for 72 h. Neither depolarization nor initiation of calcium influx was observed in the cells upon hapalindole treatment. However, the data provide evidence that hapalindoles are sodium channel-modulating neurotoxins. They inhibited veratridine-induced depolarization in a manner similar to that of neosaxitoxin. Our data suggest hapalindoles should be added to the growing number of neurotoxic secondary metabolites, such as saxitoxins and anatoxins, already known in freshwater cyanobacteria. As stable congeners, hapalindoles may be a risk in freshwater ecosystems or agricultural water usage and should therefore be considered in water quality assessment.

  12. Hapalindoles from the cyanobacterium fischerella: potential sodium channel modulators.

    Science.gov (United States)

    Cagide, Eva; Becher, Paul G; Louzao, M Carmen; Espiña, Begoña; Vieytes, Mercedes R; Jüttner, Friedrich; Botana, Luis M

    2014-10-20

    Hapalindoles make up a large group of bioactive metabolites of the cyanobacterial order Stigonematales. 12-epi-Hapalindole E isonitrile, 12-epi-hapalindole C isonitrile, 12-epi-hapalindole J isonitrile, and hapalindole L from Fischerella are acutely toxic for insect larvae; however, the biochemical targets responsible for the biological activities of hapalindoles are not understood. We describe here the electron impact mass spectra of these four hapalindole congeners; their structures were confirmed by nuclear magnetic resonance spectroscopy. In combination with the presented mass spectra of (15)N-labeled species and their retention times on a gas chromatography capillary column, a rapid and reliable determination should be possible in future research. The bioactivity of these hapalindoles was tested on mammalian cells focusing on their effects in the BE(2)-M17 excitable human neuroblastoma cell line. The fluorescent dye Alamar Blue was applied to monitor cytotoxicity, fura-2 to evaluate changes in the cytosolic calcium concentrations, and bis-oxonol to detect effects on membrane potential. Data showed that the hapalindoles did not affect cell viability of the neuroblastoma cells, even when they were incubated for 72 h. Neither depolarization nor initiation of calcium influx was observed in the cells upon hapalindole treatment. However, the data provide evidence that hapalindoles are sodium channel-modulating neurotoxins. They inhibited veratridine-induced depolarization in a manner similar to that of neosaxitoxin. Our data suggest hapalindoles should be added to the growing number of neurotoxic secondary metabolites, such as saxitoxins and anatoxins, already known in freshwater cyanobacteria. As stable congeners, hapalindoles may be a risk in freshwater ecosystems or agricultural water usage and should therefore be considered in water quality assessment. PMID:25285689

  13. Mechanisms of sodium channel clustering and its influence on axonal impulse conduction.

    Science.gov (United States)

    Freeman, Sean A; Desmazières, Anne; Fricker, Desdemona; Lubetzki, Catherine; Sol-Foulon, Nathalie

    2016-02-01

    The efficient propagation of action potentials along nervous fibers is necessary for animals to interact with the environment with timeliness and precision. Myelination of axons is an essential step to ensure fast action potential propagation by saltatory conduction, a process that requires highly concentrated voltage-gated sodium channels at the nodes of Ranvier. Recent studies suggest that the clustering of sodium channels can influence axonal impulse conduction in both myelinated and unmyelinated fibers, which could have major implications in disease, particularly demyelinating pathology. This comprehensive review summarizes the mechanisms governing the clustering of sodium channels at the peripheral and central nervous system nodes and the specific roles of their clustering in influencing action potential conduction. We further highlight the classical biophysical parameters implicated in conduction timing, followed by a detailed discussion on how sodium channel clustering along unmyelinated axons can impact axonal impulse conduction in both physiological and pathological contexts. PMID:26514731

  14. Antiepileptic drugs targeting sodium channels: subunit and neuron-type specific interactions

    NARCIS (Netherlands)

    X. Qiao

    2013-01-01

    Certain antiepileptic drugs (e.g. carbamazepine and lamotrigine) block sodium channels in an use-dependent manner and this mechanism contributes to the anti-convulsant properties of these drugs. There are, however, subtle differences in sodium current blocking properties of the antiepileptic drugs w

  15. Modification of sodium and potassium channel kinetics by diethyl ether and studies on sodium channel inactivation in the crayfish giant axon membrane

    Energy Technology Data Exchange (ETDEWEB)

    Bean, Bruce Palmer

    1979-01-01

    The effects of ether and halothane on membrane currents in the voltage clamped crayfish giant axon membrane were investigated. Concentrations of ether up to 300 mM and of halothane up to 32 mM had no effect on resting potential or leakage conductance. Ether and halothane reduced the size of sodium currents without changing the voltage dependence of the peak currents or their reversal potential. Ether and halothane also produced a reversible, dose-dependent speeding of sodium current decay at all membrane potentials. Ether reduced the time constants for inactivation, and also shifted the midpoint of the steady-state inactivation curve in the hyperpolarizing direction. Potassium currents were smaller with ether present, with no change in the voltage dependence of steady-state currents. The activation of potassium channels was faster with ether present. There was no apparent change in the capacitance of the crayfish giant axon membrane with ether concentrations of up to 100 mM. Experiments on sodium channel inactivation kinetics were performed using 4-aminopyridine to block potassium currents. Sodium currents decayed with a time course generally fit well by a single exponential. The time constant of decay was a steep function of voltage, especially in the negative resistance region of the peak current vs voltage relation.The time course of inactivation was very similar to that of the decay of the current at the same potential. The measurement of steady-state inactivation curves with different test pulses showed no shifts along the voltage asix. The voltage-dependence of the integral of sodium conductance was measured to test models of sodium channel inactivation in which channels must open before inactivating; the results appear inconsistent with some of the simplest cases of such models.

  16. Identification of sodium channel isoforms that mediate action potential firing in lamina I/II spinal cord neurons

    Directory of Open Access Journals (Sweden)

    Smith Paula L

    2011-09-01

    Full Text Available Abstract Background Voltage-gated sodium channels play key roles in acute and chronic pain processing. The molecular, biophysical, and pharmacological properties of sodium channel currents have been extensively studied for peripheral nociceptors while the properties of sodium channel currents in dorsal horn spinal cord neurons remain incompletely understood. Thus far, investigations into the roles of sodium channel function in nociceptive signaling have primarily focused on recombinant channels or peripheral nociceptors. Here, we utilize recordings from lamina I/II neurons withdrawn from the surface of spinal cord slices to systematically determine the functional properties of sodium channels expressed within the superficial dorsal horn. Results Sodium channel currents within lamina I/II neurons exhibited relatively hyperpolarized voltage-dependent properties and fast kinetics of both inactivation and recovery from inactivation, enabling small changes in neuronal membrane potentials to have large effects on intrinsic excitability. By combining biophysical and pharmacological channel properties with quantitative real-time PCR results, we demonstrate that functional sodium channel currents within lamina I/II neurons are predominantly composed of the NaV1.2 and NaV1.3 isoforms. Conclusions Overall, lamina I/II neurons express a unique combination of functional sodium channels that are highly divergent from the sodium channel isoforms found within peripheral nociceptors, creating potentially complementary or distinct ion channel targets for future pain therapeutics.

  17. Neurotoxins and their binding areas on voltage-gated sodium channels

    Directory of Open Access Journals (Sweden)

    Marijke eStevens

    2011-11-01

    Full Text Available Voltage-gated Sodium Channels (VGSCs are large transmembrane proteins that conduct sodium ions across the membrane and by doing so they generate signals of communication between many kinds of tissues. They are responsible for the generation and propagation of action potentials in excitable cells, in close collaboration with other channels like potassium channels. Genetic defects in sodium channel genes therefore can cause a wide variety of diseases, generally called ‘channelopathies’.The first insights into the mechanism of action potentials and the involvement of sodium channels originated from Hodgkin and Huxley for which they were awarded the Nobel Prize in 1963. Until now, these concepts still form the basis for understanding the functioning of VGSCs. When VGSCs sense a sufficient change in membrane potential, they are activated and will generate a massive influx of sodium ions. Immediately after, channels will start inactivating and currents decrease. In the inactivated state channels stay refractory for any new stimulus and they must return to the closed state before being susceptible to any new depolarization. On the other hand, studies with neurotoxins like tetrodotoxin (TTX and saxitoxin (STX also contributed largely to our today’s understanding of the structure and function of ion channels and specifically of VGSCs. Moreover, neurotoxins acting on ion channels turned out to be valuable tools in the development of new drugs for the enormous range of diseases in which ion channels are involved. A recent example of a synthetic neurotoxin that made it to the market is ziconotide (Prialt®, Elan. The original peptide, -MVIIA, is derived from the cone snail Conus magus and now FDA/EMEA-approved for the management of severe chronic pain by blocking the N-type voltage-gated calcium channels in neurons.This review focuses on the current status of research on neurotoxins acting on VGSC, their contribution to further unravel the

  18. Neurotoxins and their binding areas on voltage-gated sodium channels.

    Science.gov (United States)

    Stevens, Marijke; Peigneur, Steve; Tytgat, Jan

    2011-01-01

    Voltage-gated sodium channels (VGSCs) are large transmembrane proteins that conduct sodium ions across the membrane and by doing so they generate signals of communication between many kinds of tissues. They are responsible for the generation and propagation of action potentials in excitable cells, in close collaboration with other channels like potassium channels. Therefore, genetic defects in sodium channel genes can cause a wide variety of diseases, generally called "channelopathies." The first insights into the mechanism of action potentials and the involvement of sodium channels originated from Hodgkin and Huxley for which they were awarded the Nobel Prize in 1963. These concepts still form the basis for understanding the function of VGSCs. When VGSCs sense a sufficient change in membrane potential, they are activated and consequently generate a massive influx of sodium ions. Immediately after, channels will start to inactivate and currents decrease. In the inactivated state, channels stay refractory for new stimuli and they must return to the closed state before being susceptible to a new depolarization. On the other hand, studies with neurotoxins like tetrodotoxin (TTX) and saxitoxin (STX) also contributed largely to our today's understanding of the structure and function of ion channels and of VGSCs specifically. Moreover, neurotoxins acting on ion channels turned out to be valuable lead compounds in the development of new drugs for the enormous range of diseases in which ion channels are involved. A recent example of a synthetic neurotoxin that made it to the market is ziconotide (Prialt(®), Elan). The original peptide, ω-MVIIA, is derived from the cone snail Conus magus and now FDA/EMA-approved for the management of severe chronic pain by blocking the N-type voltage-gated calcium channels in pain fibers. This review focuses on the current status of research on neurotoxins acting on VGSC, their contribution to further unravel the structure and function of

  19. Sodium ion channel mutations in glioblastoma patients correlate with shorter survival

    Directory of Open Access Journals (Sweden)

    Velculescu Victor E

    2011-02-01

    Full Text Available Abstract Background Glioblastoma Multiforme (GBM is the most common and invasive astrocytic tumor associated with dismal prognosis. Treatment for GBM patients has advanced, but the median survival remains a meager 15 months. In a recent study, 20,000 genes from 21 GBM patients were sequenced that identified frequent mutations in ion channel genes. The goal of this study was to determine whether ion channel mutations have a role in disease progression and whether molecular targeting of ion channels is a promising therapeutic strategy for GBM patients. Therefore, we compared GBM patient survival on the basis of presence or absence of mutations in calcium, potassium and sodium ion transport genes. Cardiac glycosides, known sodium channel inhibitors, were then tested for their ability to inhibit GBM cell proliferation. Results Nearly 90% of patients showed at least one mutation in ion transport genes. GBM patients with mutations in sodium channels showed a significantly shorter survival compared to patients with no sodium channel mutations, whereas a similar comparison based on mutational status of calcium or potassium ion channel mutations showed no survival differences. Experimentally, targeting GBM cells with cardiac glycosides such as digoxin and ouabain demonstrated preferential cytotoxicity against U-87 and D54 GBM cells compared to non-tumor astrocytes (NTAs. Conclusions These pilot studies of GBM patients with sodium channel mutations indicate an association with a more aggressive disease and significantly shorter survival. Moreover, inhibition of GBM cells by ion channel inhibitors such as cardiac glycosides suggest a therapeutic strategy with relatively safe drugs for targeting GBM ion channel mutations. Key Words: glioblastoma multiforme, ion channels, mutations, small molecule inhibitors, cardiac glycosides.

  20. A Unified Channel Charges Expression for Analytic MOSFET Modeling

    Directory of Open Access Journals (Sweden)

    Hugues Murray

    2012-01-01

    Full Text Available Based on a 1D Poissons equation resolution, we present an analytic model of inversion charges allowing calculation of the drain current and transconductance in the Metal Oxide Semiconductor Field Effect Transistor. The drain current and transconductance are described by analytical functions including mobility corrections and short channel effects (CLM, DIBL. The comparison with the Pao-Sah integral shows excellent accuracy of the model in all inversion modes from strong to weak inversion in submicronics MOSFET. All calculations are encoded with a simple C program and give instantaneous results that provide an efficient tool for microelectronics users.

  1. The role of sodium channels in the mechanism of action of antidepressants and mood stabilizers.

    Science.gov (United States)

    Bourin, Michel; Chenu, Franck; Hascoët, Martine

    2009-11-01

    Antidepressant drugs modify in different ways the activity of neurons, by increasing monoamines levels and by modulating ion channels. Sodium channels are molecular targets for antiepileptic drugs, which can also be mood stabilizers (i.e. lamotrigine, topiramate, phenytoin, carbamazepine, valproic acid). After a short overview on the sodium channels and the interaction with antidepressants and mood stabilizers, a comparison of the activity of both antidepressants and mood stabilizers with the addition of veratrine (sodium channel opener) on the forced swimming test (FST) in mice was presented. By comparing the antidepressant-like effect of the antidepressants (paroxetine, imipramine and desipramine) with the one of anticonvulsants (lamotrigine, phenytoin and topiramate) on the FST, it seems that the mechanism of action of anticonvulsants and antidepressants are different, because veratrine limits the activity of anticonvulsants but not of antidepressants. The anticonvulsants topiramate and phenytoin reduce the immobility time in the FST in a range of time similar to those induced by antidepressants, suggesting that the FST could be sensitive to both drugs. The magnitude of antidepressant-like effect of the lamotrigine (acting through an increase in monoaminergic neurotransmission and a blockade of sodium channels) in the FST is greater than what is obtained after administration of the other drugs, suggesting that this dual activity could be used as an augmentation strategy. Authors conclude that the development of new drugs acting on sodium channels could potentially be of interest as antidepressants, but also as augmentation strategies for classical antidepressants.

  2. Effect of sodium channel abundance on Drosophila development, reproductive capacity and aging

    OpenAIRE

    Garber, Graham; Smith, Lee Ann; Reenan, Robert A.; Rogina, Blanka

    2012-01-01

    The voltage-gated Na+ channels (VGSC) are complex membrane proteins responsible for generation and propagation of the electrical signals through the brain, the skeletal muscle and the heart. The levels of sodium channels affect behavior and physical activity. This is illustrated by the maleless mutant allele (mlenapts) in Drosophila, where the decreased levels of voltage-gated Na+ channels cause temperature-sensitive paralysis.

  3. Role of Sodium Channel on Cardiac Action Potential

    Directory of Open Access Journals (Sweden)

    S. H. Sabzpoushan

    2012-06-01

    Full Text Available Sudden cardiac death is a major cause of death worldwide. In most cases, it's caused by abnormal action potential propagation that leads to cardiac arrhythmia. The aim of this article is to study the abnormal action potential propagation through sodium ion concentration variations. We use a new electrophysiological model that is both detailed and computationally efficient. This efficient model is based on the partial differential equation method. The central finite difference method is used for numerical solving of the two-dimensional (2D wave propagation equation. Simulations are implemented in two stages, as a single cardiac cell and as a two-dimensional grid of cells. In both stages, the normal action potential formation in case of a single cell and it's normal propagation in case of a two-dimensional grid of cells were simulated with nominal sodium ion conductance. Then, the effect of sodium ion concentration on the action potential signal was studied by reducing the sodium ion conductance. It is concluded that reducing the sodium ion conductance, decreases both passing ability and conduction velocity of the action potential wave front.

  4. Genetic and environmental factors in cardiac sodium channel disease

    NARCIS (Netherlands)

    Y. Mizusawa

    2016-01-01

    Cardiac sodium channelopathies, such as long QT syndrome type3 (LQT3), Brugada syndrome (BrS) and cardiac conduction disease (CCD), are heritable diseases associated with mutations in the SCN5A gene and sudden cardiac death. They were classically thought to be a monogenic disease. However, while LQT

  5. Analgesic activity of a novel use-dependent sodium channel blocker, crobenetine, in mono-arthritic rats

    OpenAIRE

    Laird, J M A; Carter, A J; Grauert, M; Cervero, F

    2001-01-01

    Although sodium channel blockers are effective analgesics in neuropathic pain, their effectiveness in inflammatory pain has been little studied. Sodium channels are substantially up-regulated in inflamed tissue, which suggests they play a role in maintenance of chronic inflammatory pain. We have examined the effects of sodium channel blockers on mobility, joint hyperalgesia and inflammation induced by complete Freund's adjuvant injected in one ankle joint of adult rats. The clinically effecti...

  6. The epithelial sodium channel mediates the directionality of galvanotaxis in human keratinocytes

    OpenAIRE

    Yang, Hsin-ya; Charles, Roch-Philippe; Hummler, Edith; Baines, Deborah L.; Isseroff, R. Rivkah

    2013-01-01

    Cellular directional migration in an electric field (galvanotaxis) is one of the mechanisms guiding cell movement in embryogenesis and in skin epidermal repair. The epithelial sodium channel (ENaC), in addition to its function of regulating sodium transport in kidney, has recently been found to modulate cell locomotory speed. Here we tested whether ENaC has an additional function of mediating the directional migration of galvanotaxis in keratinocytes. Genetic depletion of ENaC completely bloc...

  7. Charge Transfer Channels in Formation of Exciplex in Polymer Blends

    Institute of Scientific and Technical Information of China (English)

    DOU Fei; ZHANG Xin-Ping

    2011-01-01

    The strong dependence of photoluminescence of charge transfer excited states or exciplex in a blend film of poly(9,9'-dioctylBuorene-co-benzothiadiazole) (F8BT) and poly(9,9'-dioctyl6uorene-co-bis-N,N'-(4-butylphenyl)-bis-N,N'-phenyl-l,4- phenylenediamine) (PFB) on the excitation wavelengths and morphology is investigated. The experimental results reveal that electron transfer in the LUMOs from PFB to F8BT is more efficient than hole transfer in the HOMOs from PFB to F8BT for the formation of exciplex at the interfacial junctions between these two types of molecules in the blend Sim. Furthermore, energy transfer from the blue-emitting PFB to the green-emitting F8BT at the interfaces introduces an additional two-step channel and thus enhances the formation of an exciplex. This is important for understanding of charge generation and separation in organic bulk heterojunctions and for design of optoelectronic devices.%@@ The strong dependence of photoluminescence of charge transfer excited states or exciplex in a blend film of poly(9,9'-dioctylfluorene-co-benzothiadiazole)(F8BT)and poly(9,9'-dioctylfluorene-co-bis-N,N'-(4-butylphenyl)-bis-N,N'-phenyl-1,4-phenylenediamine)(PFB)on the excitation wavelengths and morphology is investigated.The experimental results reveal that electron transfer in the LUMOs from PFB to F8BT is more efficient than hole transfer in the HOMOs from PFB to F8BT for the formation of exciplex at the interfacial junctions between these two types of molecules in the blend film.Furthermore,energy transfer from the blue-emitting PFB to the green-emitting F8BT at the interfaces introduces an additional two-step channel and thus enhances the formation of an exciplex.This is important for understanding of charge generation and separation in organic bulk heterojunctions and for design of optoelectronic devices.

  8. Comparative effects of sodium channel blockers in short term rat whole embryo culture

    Energy Technology Data Exchange (ETDEWEB)

    Nilsson, Mats F, E-mail: Mats.Nilsson@farmbio.uu.se [Department of Pharmaceutical Biosciences, Uppsala University (Sweden); Sköld, Anna-Carin; Ericson, Ann-Christin; Annas, Anita; Villar, Rodrigo Palma [AstraZeneca R and D Södertälje (Sweden); Cebers, Gvido [AstraZeneca R and D, iMed, 141 Portland Street, Cambridge, MA 02139 (United States); Hellmold, Heike; Gustafson, Anne-Lee [AstraZeneca R and D Södertälje (Sweden); Webster, William S [Department of Anatomy and Histology, University of Sydney (Australia)

    2013-10-15

    This study was undertaken to examine the effect on the rat embryonic heart of two experimental drugs (AZA and AZB) which are known to block the sodium channel Nav1.5, the hERG potassium channel and the L-type calcium channel. The sodium channel blockers bupivacaine, lidocaine, and the L-type calcium channel blocker nifedipine were used as reference substances. The experimental model was the gestational day (GD) 13 rat embryo cultured in vitro. In this model the embryonic heart activity can be directly observed, recorded and analyzed using computer assisted image analysis as it responds to the addition of test drugs. The effect on the heart was studied for a range of concentrations and for a duration up to 3 h. The results showed that AZA and AZB caused a concentration-dependent bradycardia of the embryonic heart and at high concentrations heart block. These effects were reversible on washout. In terms of potency to cause bradycardia the compounds were ranked AZB > bupivacaine > AZA > lidocaine > nifedipine. Comparison with results from previous studies with more specific ion channel blockers suggests that the primary effect of AZA and AZB was sodium channel blockage. The study shows that the short-term rat whole embryo culture (WEC) is a suitable system to detect substances hazardous to the embryonic heart. - Highlights: • Study of the effect of sodium channel blocking drugs on embryonic heart function • We used a modified method rat whole embryo culture with image analysis. • The drugs tested caused a concentration dependent bradycardia and heart block. • The effect of drugs acting on multiple ion channels is difficult to predict. • This method may be used to detect cardiotoxicity in prenatal development.

  9. On the multiple roles of the voltage gated sodium channel β1 subunit in genetic diseases

    Directory of Open Access Journals (Sweden)

    Debora eBaroni

    2015-05-01

    Full Text Available Voltage-gated sodium channels are intrinsic plasma membrane proteins that initiate the action potential in electrically excitable cells. They are composed of a pore-forming α-subunit and associated β-subunits. The β1-subunit was the first accessory subunit to be cloned. It can be important for controlling cell excitability and modulating multiple aspects of sodium channel physiology. Mutations of β1 are implicated in a wide variety of inherited pathologies, including epilepsy and cardiac conduction diseases. This review summarizes β1-subunit related channelopathies pointing out the current knowledge concerning their genetic background and their underlying molecular mechanisms.

  10. Mass and charge transport in micro and nanofluidic channels

    DEFF Research Database (Denmark)

    Mortensen, Niels Asger; Olesen, Laurits Højgaard; Okkels, Fridolin;

    2007-01-01

    We consider laminar flow of incompressible electrolytes in long, straight channels driven by pressure and electroosmosis. We use aHilbert space eigenfunction expansion to address the general problem of an arbitrary cross section and obtain general results in linear-response theory for the mass and...... charge transport coefficients that satisfy Onsager relations. In the limit of nonoverlapping Debye layers the transport coefficients are simply expressed in terms of parameters of the electrolyte as well as the hydraulic radiusR ¼ 2A=P with Aand P being the cross-sectional area and perimeter......, respectively. In particular, we consider the limits of thin nonoverlapping as well as strongly overlapping Debye layers, respectively, and calculate the corrections to the hydraulic resistance due to electrohydrodynamic interactions....

  11. Local anesthetic and antiepileptic drug access and binding to a bacterial voltage-gated sodium channel.

    Science.gov (United States)

    Boiteux, Céline; Vorobyov, Igor; French, Robert J; French, Christopher; Yarov-Yarovoy, Vladimir; Allen, Toby W

    2014-09-01

    Voltage-gated sodium (Nav) channels are important targets in the treatment of a range of pathologies. Bacterial channels, for which crystal structures have been solved, exhibit modulation by local anesthetic and anti-epileptic agents, allowing molecular-level investigations into sodium channel-drug interactions. These structures reveal no basis for the "hinged lid"-based fast inactivation, seen in eukaryotic Nav channels. Thus, they enable examination of potential mechanisms of use- or state-dependent drug action based on activation gating, or slower pore-based inactivation processes. Multimicrosecond simulations of NavAb reveal high-affinity binding of benzocaine to F203 that is a surrogate for FS6, conserved in helix S6 of Domain IV of mammalian sodium channels, as well as low-affinity sites suggested to stabilize different states of the channel. Phenytoin exhibits a different binding distribution owing to preferential interactions at the membrane and water-protein interfaces. Two drug-access pathways into the pore are observed: via lateral fenestrations connecting to the membrane lipid phase, as well as via an aqueous pathway through the intracellular activation gate, despite being closed. These observations provide insight into drug modulation that will guide further developments of Nav inhibitors. PMID:25136136

  12. Structure of membrane-active toxin from crab spider Heriaeus melloteei suggests parallel evolution of sodium channel gating modifiers in Araneomorphae and Mygalomorphae.

    Science.gov (United States)

    Berkut, Antonina A; Peigneur, Steve; Myshkin, Mikhail Yu; Paramonov, Alexander S; Lyukmanova, Ekaterina N; Arseniev, Alexander S; Grishin, Eugene V; Tytgat, Jan; Shenkarev, Zakhar O; Vassilevski, Alexander A

    2015-01-01

    We present a structural and functional study of a sodium channel activation inhibitor from crab spider venom. Hm-3 is an insecticidal peptide toxin consisting of 35 amino acid residues from the spider Heriaeus melloteei (Thomisidae). We produced Hm-3 recombinantly in Escherichia coli and determined its structure by NMR spectroscopy. Typical for spider toxins, Hm-3 was found to adopt the so-called "inhibitor cystine knot" or "knottin" fold stabilized by three disulfide bonds. Its molecule is amphiphilic with a hydrophobic ridge on the surface enriched in aromatic residues and surrounded by positive charges. Correspondingly, Hm-3 binds to both neutral and negatively charged lipid vesicles. Electrophysiological studies showed that at a concentration of 1 μm Hm-3 effectively inhibited a number of mammalian and insect sodium channels. Importantly, Hm-3 shifted the dependence of channel activation to more positive voltages. Moreover, the inhibition was voltage-dependent, and strong depolarizing prepulses attenuated Hm-3 activity. The toxin is therefore concluded to represent the first sodium channel gating modifier from an araneomorph spider and features a "membrane access" mechanism of action. Its amino acid sequence and position of the hydrophobic cluster are notably different from other known gating modifiers from spider venom, all of which are described from mygalomorph species. We hypothesize parallel evolution of inhibitor cystine knot toxins from Araneomorphae and Mygalomorphae suborders.

  13. Expression of mRNA coding voltage - gated sodium channel α-subunit in spontaneously epileptic rat

    Institute of Scientific and Technical Information of China (English)

    DUWa; CAIJi-Qun

    2004-01-01

    OBJECTIVE Subtypes Ⅰ,Ⅱ and Ⅲ of sodium channel α- subunit mRNA were analyzed in adult rat brain of spontaneously epileptic rats, and investigated the relationship between sodium channel expression and epilepsy. METHODS Tissue samples were microdissected from occipital neocortex, CA1 and CA3 hippocampus areas and dentate gyms, observe

  14. A novel LQT3 mutation implicates the human cardiac sodium channel domain IVS6 in inactivation kinetics

    NARCIS (Netherlands)

    Groenewegen, WA; Bezzina, CR; van Tintelen, JP; Hoorntje, TM; Mannens, MMAM; Wilde, AAM; Jongsma, HJ; Rook, MB

    2003-01-01

    The Long QT3 syndrome is associated with mutations in the cardiac sodium channel gene SCN5A. Objective: The aim of the present study was the identification and functional characterization of a mutation in a family with the long QT3 syndrome. Methods: The human cardiac sodium channel gene SCN5A was s

  15. Phenotypical Manifestations of Mutations in the Genes Encoding Subunits of the Cardiac Sodium Channel

    NARCIS (Netherlands)

    Wilde, Arthur A. M.; Brugada, Ramon

    2011-01-01

    Variations in the gene encoding for the major sodium channel (Na(v)1.5) in the heart, SCN5A, has been shown to cause a number of arrhythmia syndromes (with or without structural changes in the myocardium), including the long-QT syndrome (type 3), Brugada syndrome, (progressive) cardiac conduction di

  16. Amiloride blocks lithium entry through the sodium channel thereby attenuating the resultant nephrogenic diabetes insipidus.

    NARCIS (Netherlands)

    Kortenoeven, M.L.A.; Li, Yuedan; Shaw, S.M.; Gaeggeler, H.P.; Rossier, B.C.; Wetzels, J.F.M.; Deen, P.M.T.

    2009-01-01

    Lithium therapy frequently induces nephrogenic diabetes insipidus; amiloride appears to prevent its occurrence in some clinical cases. Amiloride blocks the epithelial sodium channel (ENaC) located in the apical membrane of principal cells; hence one possibility is that ENaC is the main entry site fo

  17. Mutations in Sodium Channel Gene SCN9A and the Pain Perception Disorders

    OpenAIRE

    Marković, Danica; Janković, Radmilo; Veselinović, Ines

    2015-01-01

    Voltage-gated sodium channels (NaV) play a crucial role in development and propagation of action potentials in neurons and muscle cells. NaV1.7 channels take a special place in modern science since it is believed that they contribute to nerve hyperexcitability. Mutations of the gene SCN9A, which codes the α subunit of NaV1.7 channels, are associated with pain perception disorders (primary erythermalgia, congenital analgesia, and paroxysmal pain disorder). It is considered that the SCN9A gene ...

  18. Computational Structural Pharmacology and Toxicology of Voltage-Gated Sodium Channels.

    Science.gov (United States)

    Zhorov, B S; Tikhonov, D B

    2016-01-01

    Voltage-gated sodium channels are targets for many toxins and medically important drugs. Despite decades of intensive studies in industry and academia, atomic mechanisms of action are still not completely understood. The major cause is a lack of high-resolution structures of eukaryotic channels and their complexes with ligands. In these circumstances a useful approach is homology modeling that employs as templates X-ray structures of potassium channels and prokaryotic sodium channels. On one hand, due to inherent limitations of this approach, results should be treated with caution. In particular, models should be tested against relevant experimental data. On the other hand, docking of drugs and toxins in homology models provides a unique possibility to integrate diverse experimental data provided by mutational analysis, electrophysiology, and studies of structure-activity relations. Here we describe how homology modeling advanced our understanding of mechanisms of several classes of ligands. These include tetrodotoxins and mu-conotoxins that block the outer pore, local anesthetics that block of the inner pore, batrachotoxin that binds in the inner pore but, paradoxically, activates the channel, pyrethroid insecticides that activate the channel by binding at lipid-exposed repeat interfaces, and scorpion alpha and beta-toxins, which bind between the pore and voltage-sensing domains and modify the channel gating. We emphasize importance of experimental data for elaborating the models. PMID:27586283

  19. Venom Peptides From Cone Snails: Pharmacological Probes for Voltage-Gated Sodium Channels.

    Science.gov (United States)

    Green, B R; Olivera, B M

    2016-01-01

    The venoms of cone snails provide a rich source of neuroactive peptides (conotoxins). Several venom peptide families have been identified that are either agonists (ι- and δ-conotoxins) or antagonists (μ- and μO-conotoxins) of voltage-gated sodium channels (VGSCs). Members of these conotoxin classes have been integral in identifying and characterizing specific neurotoxin binding sites on the channel. Furthermore, given the specificity of some of these peptides for one sodium channel subtype over another, conotoxins have also proven useful in exploring differences between VGSC subtypes. This chapter summarizes the current knowledge of the structure and function based on the results of conotoxin interactions with VGSCs and correlates the peptides with the phylogeny of the Conus species from which they were derived. PMID:27586281

  20. A melanosomal two-pore sodium channel regulates pigmentation.

    Science.gov (United States)

    Bellono, Nicholas W; Escobar, Iliana E; Oancea, Elena

    2016-01-01

    Intracellular organelles mediate complex cellular functions that often require ion transport across their membranes. Melanosomes are organelles responsible for the synthesis of the major mammalian pigment melanin. Defects in melanin synthesis result in pigmentation defects, visual deficits, and increased susceptibility to skin and eye cancers. Although genes encoding putative melanosomal ion transporters have been identified as key regulators of melanin synthesis, melanosome ion transport and its contribution to pigmentation remain poorly understood. Here we identify two-pore channel 2 (TPC2) as the first reported melanosomal cation conductance by directly patch-clamping skin and eye melanosomes. TPC2 has been implicated in human pigmentation and melanoma, but the molecular mechanism mediating this function was entirely unknown. We demonstrate that the vesicular signaling lipid phosphatidylinositol bisphosphate PI(3,5)P2 modulates TPC2 activity to control melanosomal membrane potential, pH, and regulate pigmentation. PMID:27231233

  1. Molecular identity of dendritic voltage-gated sodium channels.

    Science.gov (United States)

    Lorincz, Andrea; Nusser, Zoltan

    2010-05-14

    Active invasion of the dendritic tree by action potentials (APs) generated in the axon is essential for associative synaptic plasticity and neuronal ensemble formation. In cortical pyramidal cells (PCs), this AP back-propagation is supported by dendritic voltage-gated Na+ (Nav) channels, whose molecular identity is unknown. Using a highly sensitive electron microscopic immunogold technique, we revealed the presence of the Nav1.6 subunit in hippocampal CA1 PC proximal and distal dendrites. Here, the subunit density is lower by a factor of 35 to 80 than that found in axon initial segments. A gradual decrease in Nav1.6 density along the proximodistal axis of the dendritic tree was also detected without any labeling in dendritic spines. Our results reveal the characteristic subcellular distribution of the Nav1.6 subunit, identifying this molecule as a key substrate enabling dendritic excitability. PMID:20466935

  2. Nav1.5 cardiac sodium channels, regulation and clinical implications

    Directory of Open Access Journals (Sweden)

    Henry Humberto León-Ariza

    2014-10-01

    Full Text Available Voltage-gated sodium channels constitute a group of membrane proteins widely distributed thought the body. In the heart, there are at least six different isoforms, being the Nav1.5 the most abundant. The channel is composed of an α subunit that is formed by four domains of six segments each, and four much smaller β subunits that provide stability and integrate other channels into the α subunit. The function of the Nav1.5 channel is modulated by intracellular cytoskeleton proteins, extracellular proteins, calcium concentration, free radicals, and medications, among other things. The study of the channel and its alterations has grown thanks to its association with pathogenic conditions such as Long QT syndrome, Brugada syndrome, atrial fibrillation, arrhythmogenic ventricular dysplasia and complications during ischemic processes.

  3. Ionic charge transport between blockages: Sodium cation conduction in freshly excised bulk brain tissue

    Energy Technology Data Exchange (ETDEWEB)

    Emin, David, E-mail: emin@unm.edu [Department of Physics and Astronomy, University of New Mexico, Albuquerque, NM 87131 (United States); Akhtari, Massoud [Semple Institutes for Neuroscience and Human Behavior, David Geffen School of Medicine, University of California at Los Angeles, Los Angeles, CA 90095 (United States); Ellingson, B. M. [Department of Radiology, David Geffen School of Medicine, University of California at Los Angeles, Los Angeles, CA 90095 (United States); Mathern, G. W. [Department of Neurosurgery, David Geffen School of Medicine, University of California at Los Angeles, Los Angeles, CA 90095 (United States)

    2015-08-15

    We analyze the transient-dc and frequency-dependent electrical conductivities between blocking electrodes. We extend this analysis to measurements of ions’ transport in freshly excised bulk samples of human brain tissue whose complex cellular structure produces blockages. The associated ionic charge-carrier density and diffusivity are consistent with local values for sodium cations determined non-invasively in brain tissue by MRI (NMR) and diffusion-MRI (spin-echo NMR). The characteristic separation between blockages, about 450 microns, is very much shorter than that found for sodium-doped gel proxies for brain tissue, >1 cm.

  4. Differential distribution of the sodium-activated potassium channels slick and slack in mouse brain.

    Science.gov (United States)

    Rizzi, Sandra; Knaus, Hans-Günther; Schwarzer, Christoph

    2016-07-01

    The sodium-activated potassium channels Slick (Slo2.1, KCNT2) and Slack (Slo2.2, KCNT1) are high-conductance potassium channels of the Slo family. In neurons, Slick and Slack channels are involved in the generation of slow afterhyperpolarization, in the regulation of firing patterns, and in setting and stabilizing the resting membrane potential. The distribution and subcellular localization of Slick and Slack channels in the mouse brain have not yet been established in detail. The present study addresses this issue through in situ hybridization and immunohistochemistry. Both channels were widely distributed and exhibited distinct distribution patterns. However, in some brain regions, their expression overlapped. Intense Slick channel immunoreactivity was observed in processes, varicosities, and neuronal cell bodies of the olfactory bulb, granular zones of cortical regions, hippocampus, amygdala, lateral septal nuclei, certain hypothalamic and midbrain nuclei, and several regions of the brainstem. The Slack channel showed primarily a diffuse immunostaining pattern, and labeling of cell somata and processes was observed only occasionally. The highest Slack channel expression was detected in the olfactory bulb, lateral septal nuclei, basal ganglia, and distinct areas of the midbrain, brainstem, and cerebellar cortex. In addition, comparing our data obtained from mouse brain with a previously published study on rat brain revealed some differences in the expression and distribution of Slick and Slack channels in these species. J. Comp. Neurol. 524:2093-2116, 2016. © 2015 The Authors The Journal of Comparative Neurology Published by Wiley Periodicals, Inc. PMID:26587966

  5. The hitchhiker's guide to the voltage-gated sodium channel galaxy.

    Science.gov (United States)

    Ahern, Christopher A; Payandeh, Jian; Bosmans, Frank; Chanda, Baron

    2016-01-01

    Eukaryotic voltage-gated sodium (Nav) channels contribute to the rising phase of action potentials and served as an early muse for biophysicists laying the foundation for our current understanding of electrical signaling. Given their central role in electrical excitability, it is not surprising that (a) inherited mutations in genes encoding for Nav channels and their accessory subunits have been linked to excitability disorders in brain, muscle, and heart; and (b) Nav channels are targeted by various drugs and naturally occurring toxins. Although the overall architecture and behavior of these channels are likely to be similar to the more well-studied voltage-gated potassium channels, eukaryotic Nav channels lack structural and functional symmetry, a notable difference that has implications for gating and selectivity. Activation of voltage-sensing modules of the first three domains in Nav channels is sufficient to open the channel pore, whereas movement of the domain IV voltage sensor is correlated with inactivation. Also, structure-function studies of eukaryotic Nav channels show that a set of amino acids in the selectivity filter, referred to as DEKA locus, is essential for Na(+) selectivity. Structures of prokaryotic Nav channels have also shed new light on mechanisms of drug block. These structures exhibit lateral fenestrations that are large enough to allow drugs or lipophilic molecules to gain access into the inner vestibule, suggesting that this might be the passage for drug entry into a closed channel. In this Review, we will synthesize our current understanding of Nav channel gating mechanisms, ion selectivity and permeation, and modulation by therapeutics and toxins in light of the new structures of the prokaryotic Nav channels that, for the time being, serve as structural models of their eukaryotic counterparts. PMID:26712848

  6. EFFECTS OF GLUTAMATE ON SODIUM CHANNEL IN ACUTELY DISSOCIATED HIPPOCAMPAL CA1 PYRAMIDAL NEURONS OF RATS

    Institute of Scientific and Technical Information of China (English)

    高宾丽; 伍国锋; 杨艳; 刘智飞; 曾晓荣

    2011-01-01

    Objective To observe the effects of glutamate on sodium channel in acutely dissociated hippocampal CA1 pyramidal neurons of rats.Methods Voltage-dependent sodium currents (INa) in acutely dissociated hippocampal CA1 pyramidal neurons of neonate rats were recorded by whole-cell patchclamp of the brain slice technique when a series of doses of glutamate (100-1000μmol/L) were applied.Results Different concentrations of glutamate could inhibit INa,and higher concentration of glutamate affected greater inhibitio...

  7. Synthesis and in vitro sodium channel blocking activity evaluation of novel homochiral mexiletine analogs.

    Science.gov (United States)

    Carocci, Alessia; Catalano, Alessia; Bruno, Claudio; Lentini, Giovanni; Franchini, Carlo; De Bellis, Michela; De Luca, Annamaria; Conte Camerino, Diana

    2010-03-01

    New chiral mexiletine analogs were synthesized in their optically active forms and evaluated in vitro as use-dependent blockers of skeletal muscle sodium channels. Tests carried out on sodium currents of single muscle fibers of Rana esculenta demonstrated that all of them exerted a higher use-dependent block than mexiletine. The most potent analog, (S)-3-(2,6-dimethylphenoxy)-1-phenylpropan-1-amine (S)-(5), was six-fold more potent than (R)-Mex in producing a tonic block. As observed with mexiletine, the newly synthesized compounds exhibit modest enantioselective behavior, that is more evident in 3-(2,6-dimethylphenoxy)butan-1-amine (3). PMID:19544349

  8. Venus Flytrap HKT1-Type Channel Provides for Prey Sodium Uptake into Carnivorous Plant Without Conflicting with Electrical Excitability

    Science.gov (United States)

    Böhm, J.; Scherzer, S.; Shabala, S.; Krol, E.; Neher, E.; Mueller, T.D.; Hedrich, R.

    2016-01-01

    The animal diet of the carnivorous Venus flytrap, Dionaea muscipula, contains a sodium load that enters the capture organ via an HKT1-type sodium channel, expressed in special epithelia cells on the inner trap lobe surface. DmHKT1 expression and sodium uptake activity is induced upon prey contact. Here, we analyzed the HKT1 properties required for prey sodium osmolyte management of carnivorous Dionaea. Analyses were based on homology modeling, generation of model-derived point mutants, and their functional testing in Xenopus oocytes. We showed that the wild-type HKT1 and its Na+- and K+-permeable mutants function as ion channels rather than K+ transporters driven by proton or sodium gradients. These structural and biophysical features of a high-capacity, Na+-selective ion channel enable Dionaea glands to manage prey-derived sodium loads without confounding the action potential-based information management of the flytrap. PMID:26455461

  9. Venus Flytrap HKT1-Type Channel Provides for Prey Sodium Uptake into Carnivorous Plant Without Conflicting with Electrical Excitability.

    Science.gov (United States)

    Böhm, J; Scherzer, S; Shabala, S; Krol, E; Neher, E; Mueller, T D; Hedrich, R

    2016-03-01

    The animal diet of the carnivorous Venus flytrap, Dionaea muscipula, contains a sodium load that enters the capture organ via an HKT1-type sodium channel, expressed in special epithelia cells on the inner trap lobe surface. DmHKT1 expression and sodium uptake activity is induced upon prey contact. Here, we analyzed the HKT1 properties required for prey sodium osmolyte management of carnivorous Dionaea. Analyses were based on homology modeling, generation of model-derived point mutants, and their functional testing in Xenopus oocytes. We showed that the wild-type HKT1 and its Na(+)- and K(+)-permeable mutants function as ion channels rather than K(+) transporters driven by proton or sodium gradients. These structural and biophysical features of a high-capacity, Na(+)-selective ion channel enable Dionaea glands to manage prey-derived sodium loads without confounding the action potential-based information management of the flytrap.

  10. Venus Flytrap HKT1-Type Channel Provides for Prey Sodium Uptake into Carnivorous Plant Without Conflicting with Electrical Excitability.

    Science.gov (United States)

    Böhm, J; Scherzer, S; Shabala, S; Krol, E; Neher, E; Mueller, T D; Hedrich, R

    2016-03-01

    The animal diet of the carnivorous Venus flytrap, Dionaea muscipula, contains a sodium load that enters the capture organ via an HKT1-type sodium channel, expressed in special epithelia cells on the inner trap lobe surface. DmHKT1 expression and sodium uptake activity is induced upon prey contact. Here, we analyzed the HKT1 properties required for prey sodium osmolyte management of carnivorous Dionaea. Analyses were based on homology modeling, generation of model-derived point mutants, and their functional testing in Xenopus oocytes. We showed that the wild-type HKT1 and its Na(+)- and K(+)-permeable mutants function as ion channels rather than K(+) transporters driven by proton or sodium gradients. These structural and biophysical features of a high-capacity, Na(+)-selective ion channel enable Dionaea glands to manage prey-derived sodium loads without confounding the action potential-based information management of the flytrap. PMID:26455461

  11. Pyrethroids differentially alter voltage-gated sodium channels from the honeybee central olfactory neurons.

    Directory of Open Access Journals (Sweden)

    Aklesso Kadala

    Full Text Available The sensitivity of neurons from the honey bee olfactory system to pyrethroid insecticides was studied using the patch-clamp technique on central 'antennal lobe neurons' (ALNs in cell culture. In these neurons, the voltage-dependent sodium currents are characterized by negative potential for activation, fast kinetics of activation and inactivation, and the presence of cumulative inactivation during train of depolarizations. Perfusion of pyrethroids on these ALN neurons submitted to repetitive stimulations induced (1 an acceleration of cumulative inactivation, and (2 a marked slowing of the tail current recorded upon repolarization. Cypermethrin and permethrin accelerated cumulative inactivation of the sodium current peak in a similar manner and tetramethrin was even more effective. The slow-down of channel deactivation was markedly dependent on the type of pyrethroid. With cypermethrin, a progressive increase of the tail current amplitude along with successive stimulations reveals a traditionally described use-dependent recruitment of modified sodium channels. However, an unexpected decrease in this tail current was revealed with tetramethrin. If one considers the calculated percentage of modified channels as an index of pyrethroids effects, ALNs are significantly more susceptible to tetramethrin than to permethrin or cypermethrin for a single depolarization, but this difference attenuates with repetitive activity. Further comparison with peripheral neurons from antennae suggest that these modifications are neuron type specific. Modeling the sodium channel as a multi-state channel with fast and slow inactivation allows to underline the effects of pyrethroids on a set of rate constants connecting open and inactivated conformations, and give some insights to their specificity. Altogether, our results revealed a differential sensitivity of central olfactory neurons to pyrethroids that emphasize the ability for these compounds to impair detection and

  12. Differential sensitivity of rat voltage-sensitive sodium channel isoforms to pyrazoline-type insecticides.

    Science.gov (United States)

    Silver, Kristopher S; Soderlund, David M

    2006-07-15

    Pyrazoline-type insecticides are potent inhibitors of insect and mammalian voltage-sensitive sodium channels. In mammals, there are nine sodium channel alpha subunit isoforms that have unique distributions and pharmacological properties, but no published data exist that compare the relative sensitivity of these different mammalian sodium channel isoforms to inhibition by pyrazoline-type insecticides. This study employed the Xenopus oocyte expression system to examine the relative sensitivity of rat Na(v)1.2a, Na(v)1.4, Na(v)1.5, and Na(v)1.8 sodium channel alpha subunit isoforms to the pyrazoline-type insecticides indoxacarb, DCJW, and RH 3421. Additionally, we assessed the effect of coexpression with the rat beta1 auxiliary subunit on the sensitivity of the Na(v)1.2a and Na(v)1.4 isoforms to these compounds. The relative sensitivity of the four sodium channel alpha subunits differed for each of the three compounds we examined. With DCJW, the order of sensitivity was Na(v)1.4 > Na(v)1.2a > Na(v)1.5 > Na(v)1.8. In contrast, the relative sensitivity of these isoforms to indoxacarb differed from that to DCJW: the Na(v)1.8 isoform was most sensitive, the Na(v)1.4 isoform was completely insensitive, and the sensitivities of the Na(v)1.5 and Na(v)1.2a isoforms were intermediate between these two extremes. Moreover, the pattern of sensitivity to RH 3421 among these four isoforms was different from that for either indoxacarb or DCJW: the Na(v)1.4 isoform was most sensitive to RH 3421, whereas the sensitivities of the remaining three isoforms were substantially less than that of the Na(v)1.4 isoform and were approximately equivalent. The only statistically significant effect of coexpression of either the Na(v)1.2a or Na(v)1.4 isoforms with the beta1 subunit was the modest reduction in the sensitivity of the Na(v)1.2a isoform to RH 3421. These results demonstrate that mammalian sodium channel isoforms differ in their sensitivities to pyrazoline-type insecticides.

  13. Convergent Evolution of Tetrodotoxin-Resistant Sodium Channels in Predators and Prey.

    Science.gov (United States)

    Toledo, G; Hanifin, C; Geffeney, S; Brodie, E D

    2016-01-01

    Convergent evolution of similar adaptive traits may arise from either common or disparate molecular and physiological mechanisms. The forces that determine the degree of underlying mechanistic similarities across convergent phenotypes are highly debated and poorly understood. Some garter snakes are able to consume newts that possess the channel blocking compound tetrodotoxin (TTX). Despite belonging to unrelated lineages, both the predators and prey have independently evolved remarkably similar physiological mechanisms of resistance to TTX that involve chemical and structural changes in voltage-gated sodium channels (NaV). The evolution of TTX resistance in this predator-prey pair constitutes a natural experiment that allows us to explore the causes of molecular convergence. Here, we review broad patterns of convergence at the level of amino acid changes in NaV channels of animals that evolved TTX resistance and make comparisons to known TTX-resistant channels that did not evolve under the selective pressures imposed by TTX. We conclude that convergence likely stems from the interplay of the target specificity of TTX and functional constraints of NaV that are shared among taxa. These and other factors can limit channel evolution to favor a few functionally permissible paths of adaptation, which can explain the observed predictability of changes to channel structure. By studying the functional causes of convergence in NaV channels, we can further our understanding of the role of these important channel proteins at the center of the evolution of the nervous system. PMID:27586282

  14. Study of proton polarization in charge exchange process on optically oriented sodium atoms

    International Nuclear Information System (INIS)

    Using high-power adjustable dye lasers for electron spin orientation in a charge-exchange target enables to significantly increase the proton polarization efficiency. A device is described that permits to avoid growth of the polarized proton beam emittance in a charge-exchange process in a strong magnetic field. The devise main feature is the use of an intensive source of neutral hydrogen atoms and the presence of a helium additional charge-exchange target which actualy is a proton ''source''. The helium charge-exchange cell is placed in the same magnetic field of a solenoid where a cell with oriented sodium is placed, a polarized electron being captured by a proton in the latter cell. In this case the beam at the solenoid inlet and outlet is in a neutral state; emittance growth related to the effect of end magnetic fields is not observed. The device after all prouduces polarized protons, their polarization degree is measured and the effect of various factors on polarization degree is studied. The description of the laser source and laser system is given. Measurement results have shown the beam intensity of neutral 7 keV atoms which passed through a polarizer to be 2 mA. The proton current doesn't depend. On the beeld fin the region of chrge exchange for the 8 kGs magnetic field. The degree of sodium polarization was 80% and polarized proton current approximately 70 μA at a temperature of the polarized sodium cell corresponding to the density of sodium vapar approximately 3x1013 at/cm2

  15. An external sodium ion binding site controls allosteric gating in TRPV1 channels.

    Science.gov (United States)

    Jara-Oseguera, Andres; Bae, Chanhyung; Swartz, Kenton J

    2016-01-01

    TRPV1 channels in sensory neurons are integrators of painful stimuli and heat, yet how they integrate diverse stimuli and sense temperature remains elusive. Here, we show that external sodium ions stabilize the TRPV1 channel in a closed state, such that removing the external ion leads to channel activation. In studying the underlying mechanism, we find that the temperature sensors in TRPV1 activate in two steps to favor opening, and that the binding of sodium to an extracellular site exerts allosteric control over temperature-sensor activation and opening of the pore. The binding of a tarantula toxin to the external pore also exerts control over temperature-sensor activation, whereas binding of vanilloids influences temperature-sensitivity by largely affecting the open/closed equilibrium. Our results reveal a fundamental role of the external pore in the allosteric control of TRPV1 channel gating and provide essential constraints for understanding how these channels can be tuned by diverse stimuli. PMID:26882503

  16. Cpt-cAMP activates human epithelial sodium channels via relieving self-inhibition

    OpenAIRE

    Molina, Raul; Han, Dong-Yun; Su, Xue-Feng; Zhao, Run-Zhen; Zhao, Meimi; Sharp, Gretta M.; Chang, Yongchang; Ji, Hong-Long

    2011-01-01

    External Na+ self-inhibition is an intrinsic feature of epithelial sodium channels (ENaC). Cpt-cAMP regulates heterologous guinea pig but not rat αβγ ENaC in a ligand-gated manner. We hypothesized that cpt-cAMP may eliminate the self-inhibition of human ENaC thereby open channels. Regulation of self-inhibition by this compound in oocytes was analyzed using the two-electrode voltage clamp and Ussing chamber setups. External cpt-cAMP stimulated human but not rat and murine αβγ ENaC in a dose- a...

  17. Characterization of the Prokaryotic Sodium Channel NavSp Pore with a Microfluidic Bilayer Platform.

    Directory of Open Access Journals (Sweden)

    Shimul Chandra Saha

    Full Text Available This paper describes the use of a newly-developed micro-chip bilayer platform to examine the electrophysiological properties of the prokaryotic voltage-gated sodium channel pore (Na(vSp from Silicibacter pomeroyi. The platform allows up to 6 bilayers to be analysed simultaneously. Proteoliposomes were incorporated into suspended lipid bilayers formed within the microfluidic bilayer chips. The chips provide access to bilayers from either side, enabling the fast and controlled titration of compounds. Dose-dependent modulation of the opening probability by the channel blocking drug nifedipine was measured and its IC50 determined.

  18. Sodium channel Nav1.8 immunoreactivity in painful human dental pulp

    Directory of Open Access Journals (Sweden)

    Tate S

    2005-07-01

    Full Text Available Abstract Background The tetrodotoxin-resistant voltage-gated sodium channel Nav1.8 (SNS1/PN3 is expressed by nociceptors and may play a role in pain states. Methods Using specific antibodies for immunohistochemistry, we studied Nav1.8 – immunoreactivity in human dental pulp in relation to the neuronal marker neurofilament. Human tooth pulp was extracted from teeth harvested from a total of twenty-two patients (fourteen without dental pain, eight patients with dental pain. Results Fibres immunoreactive for Nav1.8, were significantly increased on image analysis in the painful group: median (range Nav1.8 to Neurofilament % area ratio, non-painful 0.059 (0.006–0.24, painful 0.265 (0.13–0.5, P = 0.0019. Conclusion Nav1.8 sodium channels may thus represent a therapeutic target in trigeminal nerve pain states.

  19. Structure and function of the voltage sensor of sodium channels probed by a beta-scorpion toxin.

    Science.gov (United States)

    Cestèle, Sandrine; Yarov-Yarovoy, Vladimir; Qu, Yusheng; Sampieri, François; Scheuer, Todd; Catterall, William A

    2006-07-28

    Voltage sensing by voltage-gated sodium channels determines the electrical excitability of cells, but the molecular mechanism is unknown. beta-Scorpion toxins bind specifically to neurotoxin receptor site 4 and induce a negative shift in the voltage dependence of activation through a voltage sensor-trapping mechanism. Kinetic analysis showed that beta-scorpion toxin binds to the resting state, and subsequently the bound toxin traps the voltage sensor in the activated state in a voltage-dependent but concentration-independent manner. The rate of voltage sensor trapping can be fit by a two-step model, in which the first step is voltage-dependent and correlates with the outward gating movement of the IIS4 segment, whereas the second step is voltage-independent and results in shifted voltage dependence of activation of the channel. Mutations of Glu(779) in extracellular loop IIS1-S2 and both Glu(837) and Leu(840) in extracellular loop IIS3-S4 reduce the binding affinity of beta-scorpion toxin. Mutations of positively charged and hydrophobic amino acid residues in the IIS4 segment do not affect beta-scorpion toxin binding but alter voltage dependence of activation and enhance beta-scorpion toxin action. Structural modeling with the Rosetta algorithm yielded a three-dimensional model of the toxin-receptor complex with the IIS4 voltage sensor at the extracellular surface. Our results provide mechanistic and structural insight into the voltage sensor-trapping mode of scorpion toxin action, define the position of the voltage sensor in the resting state of the sodium channel, and favor voltage-sensing models in which the S4 segment spans the membrane in both resting and activated states.

  20. Structure and Function of the Voltage Sensor of Sodium Channels Probed by a β-Scorpion Toxin*S

    Science.gov (United States)

    Cestèle, Sandrine; Yarov-Yarovoy, Vladimir; Qu, Yusheng; Sampieri, François; Scheuer, Todd; Catterall, William A.

    2006-01-01

    Voltage sensing by voltage-gated sodium channels determines the electrical excitability of cells, but the molecular mechanism is unknown. β-Scorpion toxins bind specifically to neurotoxin receptor site 4 and induce a negative shift in the voltage dependence of activation through a voltage sensor-trapping mechanism. Kinetic analysis showed that β-scorpion toxin binds to the resting state, and subsequently the bound toxin traps the voltage sensor in the activated state in a voltage-dependent but concentration-independent manner. The rate of voltage sensor trapping can be fit by a two-step model, in which the first step is voltage-dependent and correlates with the outward gating movement of the IIS4 segment, whereas the second step is voltage-independent and results in shifted voltage dependence of activation of the channel. Mutations of Glu779 in extracellular loop IIS1–S2 and both Glu837 and Leu840 in extracellular loop IIS3–S4 reduce the binding affinity of β-scorpion toxin. Mutations of positively charged and hydrophobic amino acid residues in the IIS4 segment do not affect β-scorpion toxin binding but alter voltage dependence of activation and enhance β-scorpion toxin action. Structural modeling with the Rosetta algorithm yielded a three-dimensional model of the toxin-receptor complex with the IIS4 voltage sensor at the extracellular surface. Our results provide mechanistic and structural insight into the voltage sensor-trapping mode of scorpion toxin action, define the position of the voltage sensor in the resting state of the sodium channel, and favor voltage-sensing models in which the S4 segment spans the membrane in both resting and activated states. PMID:16679310

  1. Charge fluctuations and their effect on conduction in biological ion channels

    CERN Document Server

    Luchinsky, D G; Kaufman, I; McClintock, P V E; Eisenberg, R S

    2008-01-01

    The effect of fluctuations on the conductivity of ion channels is investigated. It is shown that modulation of the potential barrier at the selectivity site due to electrostatic amplification of charge fluctuations at the channel mouth exerts a leading-order effect on the channel conductivity. A Brownian dynamical model of ion motion in a channel is derived that takes into account both fluctuations at the channel mouth and vibrational modes of the wall. The charge fluctuations are modeled as a short noise flipping the height of the potential barrier. The wall fluctuations are introduced as a slow vibrational mode of protein motion that modulates ion conductance both stochastically and periodically. The model is used to estimate the contribution of the electrostatic amplification of charge fluctuations to the conductivity of ion channels.

  2. Visualizing Dermal Permeation of Sodium Channel Modulators by Mass Spectrometric Imaging

    OpenAIRE

    Eberlin, Livia S; Mulcahy, John V.; Tzabazis, Alexander; Zhang, Jialing; Liu, Huwei; Logan, Matthew M.; Roberts, Heather J.; Lee, Gordon K.; Yeomans, David C.; Du Bois, Justin; Zare, Richard N.

    2014-01-01

    Determining permeability of a given compound through human skin is a principal challenge owing to the highly complex nature of dermal tissue. We describe the application of an ambient mass spectrometry imaging method for visualizing skin penetration of sodium channel modulators, including novel synthetic analogs of natural neurotoxic alkaloids, topically applied ex vivo to human skin. Our simple and label-free approach enables successful mapping of the transverse and lateral diffusion of smal...

  3. Sodium channel Nav1.7 in vascular myocytes, endothelium, and innervating axons in human skin

    OpenAIRE

    Rice, Frank L.; Albrecht, Phillip J.; Wymer, James P.; Black, Joel A; Merkies, Ingemar SJ; Faber, Catharina G; WAXMAN, STEPHEN G.

    2015-01-01

    Background The skin is a morphologically complex organ that serves multiple complementary functions, including an important role in thermoregulation, which is mediated by a rich vasculature that is innervated by sympathetic and sensory endings. Two autosomal dominant disorders characterized by episodes of severe pain, inherited erythromelalgia (IEM) and paroxysmal extreme pain disorder (PEPD) have been directly linked to mutations that enhance the function of sodium channel Nav1.7. Pain attac...

  4. MicroRNA 16 Modulates Epithelial Sodium Channel in Human Alveolar Epithelial Cells

    OpenAIRE

    Parthasarathy, Prasanna Tamarapu; Galam, Lakshmi; Huynh, Bao; Yunus, Asfiya; Abuelenen, Toaa; Castillo, Annie; Ramanathan, Gurukumar Kollongod; Ruan, Cox; Kolliputi, Narasaiah

    2012-01-01

    Acute lung injury (ALI) is a devastating disease characterized by pulmonary edema. Removal of edema from the air spaces is a critical function of the epithelial sodium channel (ENaC) in ALI. The molecular mechanisms behind resolution of pulmonary edema are incompletely understood. MicroRNA’s (miRNA) are crucial gene regulators and are dysregulated in various diseases including ALI. Recent studies suggest that microRNA-16 (miR-16) targets serotonin transporter (SERT) involved in the serotonin ...

  5. Modulation of the Epithelial Sodium Channel (ENaC) by Bacterial Metalloproteases and Protease Inhibitors

    OpenAIRE

    Butterworth, Michael B.; Liang Zhang; Xiaoning Liu; Shanks, Robert M.; Thibodeau, Patrick H.

    2014-01-01

    The serralysin family of metalloproteases is associated with the virulence of multiple gram-negative human pathogens, including Pseudomonas aeruginosa and Serratia marcescens. The serralysin proteases share highly conserved catalytic domains and show evolutionary similarity to the mammalian matrix metalloproteases. Our previous studies demonstrated that alkaline protease (AP) from Pseudomonas aeruginosa is capable of activating the epithelial sodium channel (ENaC), leading to an increase in s...

  6. A novel anticonvulsant modulates voltage-gated sodium channel inactivation and prevents kindling-induced seizures.

    Science.gov (United States)

    Ashraf, Muhammad N; Gavrilovici, Cezar; Shah, Syed U Ali; Shaheen, Farzana; Choudhary, Muhammad I; Rahman, Atta-ur; Fahnestock, Margaret; Simjee, Shabana U; Poulter, Michael O

    2013-09-01

    Here, we explore the mechanism of action of isoxylitone (ISOX), a molecule discovered in the plant Delphinium denudatum, which has been shown to have anticonvulsant properties. Patch-clamp electrophysiology assayed the activity of ISOX on voltage-gated sodium channels (VGSCs) in both cultured neurons and brain slices isolated from controls and rats with experimental epilepsy(kindling model). Quantitative transcription polymerase chain reaction (qRT-PCR) (QPCR) assessed brain-derived neurotrophic factor (BDNF) mRNA expression in kindled rats, and kindled rats treated with ISOX. ISOX suppressed sodium current (I(Na)) showing an IC50 value of 185 nM in cultured neurons. ISOX significantly slowed the recovery from inactivation (ISOX τ = 18.7 ms; Control τ = 9.4 ms; p kindled cortical neurons, the IC50 for sodium current block was identical to that found in cultured neurons. ISOX prevented kindled stage 5 seizures and decreased the enhanced BDNF mRNA expression that is normally associated with kindling (p kindling is likely a secondary outcome that nevertheless would suppress epileptogenesis. These data show a new class of anti-seizure compound that inhibits sodium channel function and prevents the development of epileptic seizures.

  7. Possible involvement of tetrodotoxin-resistant sodium channels in cough reflex.

    Science.gov (United States)

    Kamei, Junzo; Nakanishi, Yuki; Ishikawa, Yoko; Hayashi, Shun-Suke; Asato, Megumi; Ohsawa, Masahiro

    2011-02-10

    We examined the involvement of tetrodotoxin (TTX)-resistant sodium channels in the peripheral mechanisms of the cough reflex in mice. We also examined the possibility of using ambroxol as an effective antitussive agent, and found that it produced antitussive effects through the inhibition of TTX-resistant sodium channels. The inhalation of fenvalerate, at concentrations of 0.3, 1 and 3μg/ml, for 5min produced coughs in a concentration-dependent manner. Pretreatment with tetrodotoxin, at a dose of 1μg/kg, s.c., slightly but significantly reduced the number of fenvalerate (3μg/ml)-induced coughs. However, the number of fenvalerate-induced coughs in tetorodotoxin-treated mice was still significantly greater than those in vehicle (0.4% DMSO) alone inhaled mice. On the other hand, pretreatment with tetrodotoxin, at a dose of 1μg/kg, s.c., almost completely reduced the number of citric acid (0.25M)-induced coughs to the level in vehicle (saline) alone inhaled mice. Pretreatment with ambroxol, at doses of 10, 30, 100 and 300mg/kg, p.o., dose-dependently and significantly reduced the number of fenvalerate (3μg/ml)-induced coughs. The present findings indicate that TTX-resistant sodium channels may play an important role in the enhancement of C-fiber-mediated cough pathways. Furthermore, ambroxol may prove to be a useful cough suppressant. PMID:21130084

  8. Alterations in plasma membrane promote overexpression and increase of sodium influx through epithelial sodium channel in hypertensive platelets.

    Science.gov (United States)

    Cerecedo, D; Martínez-Vieyra, Ivette; Sosa-Peinado, Alejandro; Cornejo-Garrido, Jorge; Ordaz-Pichardo, Cynthia; Benítez-Cardoza, Claudia

    2016-08-01

    Platelets are small, anucleated cell fragments that activate in response to a wide variety of stimuli, triggering a complex series of intracellular pathways leading to a hemostatic thrombus formation at vascular injury sites. However, in essential hypertension, platelet activation contributes to causing myocardial infarction and ischemic stroke. Reported abnormalities in platelet functions, such as platelet hyperactivity and hyperaggregability to several agonists, contribute to the pathogenesis and complications of thrombotic events associated with hypertension. Platelet membrane lipid composition and fluidity are determining for protein site accessibility, structural arrangement of platelet surface, and response to appropriate stimuli. The present study aimed to demonstrate whether structural and biochemical abnormalities in lipid membrane composition and fluidity characteristic of platelets from hypertensive patients influence the expression of the Epithelial Sodium Channel (ENaC), fundamental for sodium influx during collagen activation. Wb, cytometry and quantitative Reverse Transcription-Polymerase Chain Reaction (qRT-PCR) assays demonstrated ENaC overexpression in platelets from hypertensive subjects and in relation to control subjects. Additionally, our results strongly suggest a key role of β-dystroglycan as a scaffold for the organization of ENaC and associated proteins. Understanding of the mechanisms of platelet alterations in hypertension should provide valuable information for the pathophysiology of hypertension. PMID:27137675

  9. Alterations in plasma membrane promote overexpression and increase of sodium influx through epithelial sodium channel in hypertensive platelets.

    Science.gov (United States)

    Cerecedo, D; Martínez-Vieyra, Ivette; Sosa-Peinado, Alejandro; Cornejo-Garrido, Jorge; Ordaz-Pichardo, Cynthia; Benítez-Cardoza, Claudia

    2016-08-01

    Platelets are small, anucleated cell fragments that activate in response to a wide variety of stimuli, triggering a complex series of intracellular pathways leading to a hemostatic thrombus formation at vascular injury sites. However, in essential hypertension, platelet activation contributes to causing myocardial infarction and ischemic stroke. Reported abnormalities in platelet functions, such as platelet hyperactivity and hyperaggregability to several agonists, contribute to the pathogenesis and complications of thrombotic events associated with hypertension. Platelet membrane lipid composition and fluidity are determining for protein site accessibility, structural arrangement of platelet surface, and response to appropriate stimuli. The present study aimed to demonstrate whether structural and biochemical abnormalities in lipid membrane composition and fluidity characteristic of platelets from hypertensive patients influence the expression of the Epithelial Sodium Channel (ENaC), fundamental for sodium influx during collagen activation. Wb, cytometry and quantitative Reverse Transcription-Polymerase Chain Reaction (qRT-PCR) assays demonstrated ENaC overexpression in platelets from hypertensive subjects and in relation to control subjects. Additionally, our results strongly suggest a key role of β-dystroglycan as a scaffold for the organization of ENaC and associated proteins. Understanding of the mechanisms of platelet alterations in hypertension should provide valuable information for the pathophysiology of hypertension.

  10. Preclinical evaluation of marketed sodium channel blockers in a rat model of myotonia discloses promising antimyotonic drugs

    OpenAIRE

    Desaphy, Jean-François; Carbonara, Roberta; Costanza, Teresa; Conte Camerino, Diana

    2014-01-01

    Although the sodium channel blocker mexiletine is considered the first-line drug in myotonia, some patients experiment adverse effects, while others do not gain any benefit. Other antimyotonic drugs are thus needed to offer mexiletine alternatives. In the present study, we used a previously-validated rat model of myotonia congenita to compare six marketed sodium channel blockers to mexiletine. Myotonia was induced in the rat by injection of anthracen-9-carboxylic acid, a muscle chloride chann...

  11. The voltage-gated sodium channel nav1.8 is expressed in human sperm.

    Directory of Open Access Journals (Sweden)

    Antonio Cejudo-Roman

    Full Text Available The role of Na(+ fluxes through voltage-gated sodium channels in the regulation of sperm cell function remains poorly understood. Previously, we reported that several genes encoding voltage-gated Na(+ channels were expressed in human testis and mature spermatozoa. In this study, we analyzed the presence and function of the TTX-resistant VGSC α subunit Nav1.8 in human capacitated sperm cells. Using an RT-PCR assay, we found that the mRNA of the gene SCN10A, that encode Na v1.8, was abundantly and specifically expressed in human testis and ejaculated spermatozoa. The Na v1.8 protein was detected in capacitated sperm cells using three different specific antibodies against this channel. Positive immunoreactivity was mainly located in the neck and the principal piece of the flagellum. The presence of Na v1.8 in sperm cells was confirmed by Western blot. Functional studies demonstrated that the increases in progressive motility produced by veratridine, a voltage-gated sodium channel activator, were reduced in sperm cells preincubated with TTX (10 μM, the Na v1.8 antagonist A-803467, or a specific Na v1.8 antibody. Veratridine elicited similar percentage increases in progressive motility in sperm cells maintained in Ca(2+-containing or Ca(2+-free solution and did not induce hyperactivation or the acrosome reaction. Veratridine caused a rise in sperm intracellular Na(+, [Na(+]i, and the sustained phase of the response was inhibited in the presence of A-803467. These results verify that the Na(+ channel Na v1.8 is present in human sperm cells and demonstrate that this channel participates in the regulation of sperm function.

  12. Bisphenol A binds to the local anesthetic receptor site to block the human cardiac sodium channel.

    Directory of Open Access Journals (Sweden)

    Andrias O O'Reilly

    Full Text Available Bisphenol A (BPA has attracted considerable public attention as it leaches from plastic used in food containers, is detectable in human fluids and recent epidemiologic studies link BPA exposure with diseases including cardiovascular disorders. As heart-toxicity may derive from modified cardiac electrophysiology, we investigated the interaction between BPA and hNav1.5, the predominant voltage-gated sodium channel subtype expressed in the human heart. Electrophysiology studies of heterologously-expressed hNav1.5 determined that BPA blocks the channel with a K(d of 25.4±1.3 µM. By comparing the effects of BPA and the local anesthetic mexiletine on wild type hNav1.5 and the F1760A mutant, we demonstrate that both compounds share an overlapping binding site. With a key binding determinant thus identified, an homology model of hNav1.5 was generated based on the recently-reported crystal structure of the bacterial voltage-gated sodium channel NavAb. Docking predictions position both ligands in a cavity delimited by F1760 and contiguous with the DIII-IV pore fenestration. Steered molecular dynamics simulations used to assess routes of ligand ingress indicate that the DIII-IV pore fenestration is a viable access pathway. Therefore BPA block of the human heart sodium channel involves the local anesthetic receptor and both BPA and mexiletine may enter the closed-state pore via membrane-located side fenestrations.

  13. CPT-cGMP Is A New Ligand of Epithelial Sodium Channels.

    Science.gov (United States)

    Ji, Hong-Long; Nie, Hong-Guang; Chang, Yongchang; Lian, Qizhou; Liu, Shan-Lu

    2016-01-01

    Epithelial sodium channels (ENaC) are localized at the apical membrane of the epithelium, and are responsible for salt and fluid reabsorption. Renal ENaC takes up salt, thereby controlling salt content in serum. Loss-of-function ENaC mutations lead to low blood pressure due to salt-wasting, while gain-of-function mutations cause impaired sodium excretion and subsequent hypertension as well as hypokalemia. ENaC activity is regulated by intracellular and extracellular signals, including hormones, neurotransmitters, protein kinases, and small compounds. Cyclic nucleotides are broadly involved in stimulating protein kinase A and protein kinase G signaling pathways, and, surprisingly, also appear to have a role in regulating ENaC. Increasing evidence suggests that the cGMP analog, CPT-cGMP, activates αβγ-ENaC activity reversibly through an extracellular pathway in a dose-dependent manner. Furthermore, the parachlorophenylthio moiety and ribose 2'-hydroxy group of CPT-cGMP are essential for facilitating the opening of ENaC channels by this compound. Serving as an extracellular ligand, CPT-cGMP eliminates sodium self-inhibition, which is a novel mechanism for stimulating salt reabsorption in parallel to the traditional NO/cGMP/PKG signal pathway. In conclusion, ENaC may be a druggable target for CPT-cGMP, leading to treatments for kidney malfunctions in salt reabsorption. PMID:27019621

  14. tmc-1 encodes a sodium-sensitive channel required for salt chemosensation in C. elegans.

    Science.gov (United States)

    Chatzigeorgiou, Marios; Bang, Sangsu; Hwang, Sun Wook; Schafer, William R

    2013-02-01

    Transmembrane channel-like (TMC) genes encode a broadly conserved family of multipass integral membrane proteins in animals. Human TMC1 and TMC2 genes are linked to human deafness and required for hair-cell mechanotransduction; however, the molecular functions of these and other TMC proteins have not been determined. Here we show that the Caenorhabditis elegans tmc-1 gene encodes a sodium sensor that functions specifically in salt taste chemosensation. tmc-1 is expressed in the ASH polymodal avoidance neurons, where it is required for salt-evoked neuronal activity and behavioural avoidance of high concentrations of NaCl. However, tmc-1 has no effect on responses to other stimuli sensed by the ASH neurons including high osmolarity and chemical repellents, indicating a specific role in salt sensation. When expressed in mammalian cell culture, C. elegans TMC-1 generates a predominantly cationic conductance activated by high extracellular sodium but not by other cations or uncharged small molecules. Thus, TMC-1 is both necessary for salt sensation in vivo and sufficient to generate a sodium-sensitive channel in vitro, identifying it as a probable ionotropic sensory receptor. PMID:23364694

  15. Imidazol-1-ylethylindazole Voltage-Gated Sodium Channel Ligands Are Neuroprotective during Optic Neuritis in a Mouse Model of Multiple Sclerosis

    OpenAIRE

    Browne, Lorcan; Lidster, Katie; Al-Izki, Sarah; Clutterbuck, Lisa; Posada, Cristina; Chan, A. W. Edith; Riddall, Dieter; Garthwaite, John; Baker, David; Selwood, David L.

    2014-01-01

    A series of imidazol-1-ylethylindazole sodium channel ligands were developed and optimized for sodium channel inhibition and in vitro neuroprotective activity. The molecules exhibited displacement of a radiolabeled sodium channel ligand and selectivity for blockade of the inactivated state of cloned neuronal Nav channels. Metabolically stable analogue 6 was able to protect retinal ganglion cells during optic neuritis in a mouse model of multiple sclerosis.

  16. Imidazol-1-ylethylindazole voltage gated sodium (Nav) channel ligands are neuroprotective during optic neuritis in a mouse model of multiple sclerosis.

    OpenAIRE

    Browne, L.; Lidster, K.; Al-Izki, S.; Clutterbuck, L.; Posada, C.; Chan, A. E.; Riddall, D.; Garthwaite, J; Baker, D; Selwood, D. L.

    2014-01-01

    A series of imidazol-1-ylethyl)indazole sodium channel ligands were developed and optimized for sodium channel inhibition and in vitro neuroprotective activity. The molecules exhibited displacement of the radiolabelled sodium channel ligand and selectivity for blockade of the inactivated state of cloned neuronal Nav channels. A metabolically stable analogue 6 (CFM6104) was able to protect retinal ganglion cells during optic neuritis in a mouse model of multiple sclerosis.

  17. Cellular hyper-excitability caused by mutations that alter the activation process of voltage-gated sodium channels

    Directory of Open Access Journals (Sweden)

    Mohamed-Yassine eAMAROUCH

    2015-02-01

    Full Text Available Voltage-gated sodium channels (Nav are widely expressed as macro-molecular complexes in both excitable and non-excitable tissues. In excitable tissues, the upstroke of the action potential is the result of the passage of a large and rapid influx of sodium ions through these channels. NaV dysfunction has been associated with an increasingly wide range of neurological, muscular and cardiac disorders. The purpose of this review is to summarize the recently identified sodium channel mutations that are linked to hyper-excitability phenotypes and associated with the alteration of the activation process of voltage gated sodium channels. Indeed, several clinical manifestations that demonstrate an alteration of tissue excitability were recently shown to be strongly associated with the presence of mutations that affect the activation process of the voltage-gated sodium channels. These emerging genotype-phenotype correlations have expanded the clinical spectrum of sodium channelopathies to include disorders which feature a hyper-excitability phenotype that may or may not be associated with a cardiomyopathy. The p.I141V mutation in SCN4A and SCN5A, as well as its homologous p.I136V mutation in SCN9A, are interesting examples of mutations that have been linked to inherited hyperexcitability myotonia, exercise-induced polymorphic ventricular arrhythmias and erythromelalgia, respectively. Regardless of which sodium channel isoform is investigated, the substitution of the isoleucine to valine in the locus 141 induces similar modifications in the biophysical properties of the voltage-gated sodium channels by shifting the voltage-dependence of steady state activation towards more negative potentials.

  18. Wettability Modulated Charge Inversion and Ionic Transport in Nanofuidic Channels

    CERN Document Server

    Shaik, Vaseem Akram; Hossain, Syed Sahil; Chakraborty, Suman

    2015-01-01

    We unveil the role of substrate wettability on the reversal in the sign of the interfacial charge distribution in a nanochannel in presence of multivalent ions. In sharp contrast to the prevailing notion that hydrophobic interactions may trivially augment the effective surface charge, we demonstrate that the interplay between surface hydrophobicity and interfacial electrostatics may result in a decrease in the effective interfacial potential, and a consequent charge inversion over regimes of low surface charges. We also show that this phenomenon, in tandem with the interfacial hydrodynamics may non-trivially lead to either augmentation or attenuation or even reversal of the net streaming current, depending on the relevant physical scales involved. These results, supported by Molecular Dynamics simulations and experimental data, may bear far ranging consequences in understanding complex biophysical processes and designing nanofluidic devices and systems involving multivalent counterions.

  19. Inherited Cardiac Diseases Caused by Mutations in the Nav1.5 Sodium Channel

    DEFF Research Database (Denmark)

    Tfelt-Hansen, Jacob; Winkel, Bo Gregers; Grunnet, Morten;

    2009-01-01

    Cardiac Diseases Caused by SCN5A Mutations. A prerequisite for a normal cardiac function is a proper generation and propagation of electrical impulses. Contraction of the heart is obtained through a delicate matched transmission of the electrical impulses. A pivotal element of the impulse...... propagation is the depolarizing sodium current, responsible for the initial depolarization of the cardiomyocytes. Recent research has shown that mutations in the SCN5A gene, encoding the cardiac sodium channel Nav1.5, are associated with both rare forms of ventricular arrhythmia, as well as the most frequent...... form of arrhythmia, atrial fibrillation (AF). In this comprehensive review, we describe the functional role of Nav1.5 and its associated proteins in propagation and depolarization both in a normal- and in a pathophysiological setting. Furthermore, several of the arrhythmogenic diseases, such as long...

  20. PROPERTIES OF VOLTAGE-GATED SODIUM CHANNELS IN DEVELOPING AUDITORY NEURONS OF THE MOUSE IN VITRO

    Institute of Scientific and Technical Information of China (English)

    2003-01-01

    Objective. To investigate the properties of voltage-gated sodium (Na+) channels in developing auditoryneurons during early postnatal stages in the mammalian central nervous system.Methods. Using the whole-cell voltage-clamp technique, we have studied changes in the electrophysi-ological properties of Na+ channels in the principal neurons of the medial nucleus of the trapezoid body (MNTB).Results. We found that MNTB neurons already express functional Na+ channels at postnatal day 1 (P1),and that channel density begins to increase at P5 when the neurons receive synaptic innervation andreach its maximum (~3 fold) at P11 when functional hearing onsets. These changes were paralleled byan age-dependent acceleration in both inactivation and recovery from inactivation. In contrast, there wasvery little alteration in the voltage-dependence of inactivation.Conclusion. These profound changes in the properties of voltage-gated Na+ channels may increase theexcitability of MNTB neurons and enhance their phase-locking fidelity and capacity during high-frequencysynaptic transmission.

  1. Kinetic changes and modulation by carbamazepine on voltage-gated sodium channels in rat CA1 neurons after epilepsy.

    NARCIS (Netherlands)

    G. Sun; T.R. Werkman; W.J. Wadman

    2006-01-01

    AIM: To study whether the functional properties of sodium channels, and subsequently the channel modulation by carbamazepine (CBZ) in hippocampal CA1 neurons can be changed after epileptic seizures. METHODS: We used the acutely dissociated hippocampal CA1 pyramidal cells from epilepsy model rats 3 w

  2. Entropically induced asymmetric passage times of charged tracers across corrugated channels

    Energy Technology Data Exchange (ETDEWEB)

    Malgaretti, Paolo, E-mail: malgaretti@is.mpg.de [Max-Planck-Institut für Intelligente Systeme, Heisenbergstr. 3, D-70569 Stuttgart (Germany); IV Institut für Theoretische Physik, Universität Stuttgart, Pfaffenwaldring 57, D-70569 Stuttgart (Germany); Department de Fisica Fonamental, Universitat de Barcelona, Barcelona (Spain); Pagonabarraga, Ignacio; Miguel Rubi, J. [Department de Fisica Fonamental, Universitat de Barcelona, Barcelona (Spain)

    2016-01-21

    We analyze the diffusion of charged and neutral tracers suspended in an electrolyte embedded in a channel of varying cross section. Making use of systematic approximations, the diffusion equation governing the motion of tracers is mapped into an effective 1D equation describing the dynamics along the longitudinal axis of the channel where its varying-section is encoded as an effective entropic potential. This simplified approach allows us to characterize tracer diffusion under generic confinement by measuring their mean first passage time (MFPT). In particular, we show that the interplay between geometrical confinement and electrostatic interactions strongly affect the MFTP of tracers across corrugated channels hence leading to alternative means to control tracers translocation across charged pores. Finally, our results show that the MFPTs of a charged tracer in opposite directions along an asymmetric channel may differ We expect our results to be relevant for biological as well synthetic devices whose dynamics is controlled by the detection of diluted tracers.

  3. Entropically induced asymmetric passage times of charged tracers across corrugated channels

    Science.gov (United States)

    Malgaretti, Paolo; Pagonabarraga, Ignacio; Miguel Rubi, J.

    2016-01-01

    We analyze the diffusion of charged and neutral tracers suspended in an electrolyte embedded in a channel of varying cross section. Making use of systematic approximations, the diffusion equation governing the motion of tracers is mapped into an effective 1D equation describing the dynamics along the longitudinal axis of the channel where its varying-section is encoded as an effective entropic potential. This simplified approach allows us to characterize tracer diffusion under generic confinement by measuring their mean first passage time (MFPT). In particular, we show that the interplay between geometrical confinement and electrostatic interactions strongly affect the MFTP of tracers across corrugated channels hence leading to alternative means to control tracers translocation across charged pores. Finally, our results show that the MFPTs of a charged tracer in opposite directions along an asymmetric channel may differ We expect our results to be relevant for biological as well synthetic devices whose dynamics is controlled by the detection of diluted tracers.

  4. Charge exchange and energy loss of slowed down heavy ions channeled in silicon crystals

    International Nuclear Information System (INIS)

    This work is devoted to the study of charge exchange processes and of the energy loss of highly charged heavy ions channeled in thin silicon crystals. The two first chapters present the techniques of heavy ion channeling in a crystal, the ion-electron processes and the principle of our simulations (charge exchange and trajectory of channeled ions). The next chapters describe the two experiments performed at the GSI facility in Darmstadt, the main results of which follow: the probability per target atom of the mechanical capture (MEC) of 20 MeV/u U91+ ions as a function of the impact parameter (with the help of our simulations), the observation of the strong polarization of the target electron gas by the study of the radiative capture and the slowing down of Pb81+ ions from 13 to 8,5 MeV/u in channeling conditions for which electron capture is strongly reduced. (author)

  5. Kinetic changes and modulation by carbamazepine on voltage-gated sodium channels in rat CA1 neurons after epilepsy

    Institute of Scientific and Technical Information of China (English)

    Guang-chun SUN; Taco WERKMAN; Wytse J WADMAN

    2006-01-01

    Aim: To study whether the functional properties of sodium channels, and subsequently the channel modulation by carbamazepine (CBZ) in hippocampal CA1 neurons can be changed after epileptic seizures. Methods: We used the acutely dissociated hippocampal CA1 pyramidal cells from epilepsy model rats 3 weeks and 3 months respectively after kainate injection, and whole-cell voltage-clamp techniques. Results: After long-term epileptic seizures, both sodium channel voltage-dependence of activation and steady-state inactivation shifted to more hyperpolarizing potentials, which resulted in the enlarged window current; the membrane density of sodium current decreased and the time constant of recovery from inactivation increased. CBZ displayed unchanged efficacy on sodium channels, with a similar binding rate to them, except that at higher concentrations, the voltage shift of inactivation was reduced. For the short-term kainate model rats, no differences were detected between the control and epilepsy groups. Conclusion: These results indicate that the properties of sodium channels in acutely dissociated hippocampal neurons could be changed following long-term epilepsy, but the alternation might not be enough to induce the channel resistance to CBZ.

  6. Hlf is a genetic modifier of epilepsy caused by voltage-gated sodium channel mutations.

    Science.gov (United States)

    Hawkins, Nicole A; Kearney, Jennifer A

    2016-01-01

    Mutations in voltage-gated sodium channel genes cause several types of human epilepsies. Often, individuals with the same sodium channel mutation exhibit diverse phenotypes. This suggests that factors beyond the primary mutation influence disease severity, including genetic modifiers. Mouse epilepsy models with voltage-gated sodium channel mutations exhibit strain-dependent phenotype variability, supporting a contribution of genetic modifiers in epilepsy. The Scn2a(Q54) (Q54) mouse model has a strain-dependent epilepsy phenotype. Q54 mice on the C57BL/6J (B6) strain exhibit delayed seizure onset and improved survival compared to [B6xSJL/J]F1.Q54 mice. We previously mapped two dominant modifier loci that influence Q54 seizure susceptibility and identified Hlf (hepatic leukemia factor) as a candidate modifier gene at one locus. Hlf and other PAR bZIP transcription factors had previously been associated with spontaneous seizures in mice thought to be caused by down-regulation of the pyridoxine pathway. An Hlf targeted knockout mouse model was used to evaluate the effect of Hlf deletion on Q54 phenotype severity. Hlf(KO/KO);Q54 double mutant mice exhibited elevated frequency and reduced survival compared to Q54 controls. To determine if direct modulation of the pyridoxine pathway could alter the Q54 phenotype, mice were maintained on a pyridoxine-deficient diet for 6 weeks. Dietary pyridoxine deficiency resulted in elevated seizure frequency and decreased survival in Q54 mice compared to control diet. To determine if Hlf could modify other epilepsies, Hlf(KO/+) mice were crossed with the Scn1a(KO/+) Dravet syndrome mouse model to examine the effect on premature lethality. Hlf(KO/+);Scn1a(KO/+) offspring exhibited decreased survival compared to Scn1a(KO/+) controls. Together these results demonstrate that Hlf is a genetic modifier of epilepsy caused by voltage-gated sodium channel mutations and that modulation of the pyridoxine pathway can also influence phenotype

  7. Inhibition of collagen synthesis by select calcium and sodium channel blockers can be mitigated by ascorbic acid and ascorbyl palmitate

    OpenAIRE

    Ivanov, Vadim; Ivanova, Svetlana; KALINOVSKY, TATIANA; NIEDZWIECKI, ALEKSANDRA; RATH, MATTHIAS

    2016-01-01

    Calcium, sodium and potassium channel blockers are widely prescribed medications for a variety of health problems, most frequently for cardiac arrhythmias, hypertension, angina pectoris and other disorders. However, chronic application of channel blockers is associated with numerous side effects, including worsening cardiac pathology. For example, nifedipine, a calcium-channel blocker was found to be associated with increased mortality and increased risk for myocardial infarction. In addition...

  8. Molecular insights into the local anesthetic receptor within voltage-gated sodium channels using hydroxylated analogues of mexiletine

    Directory of Open Access Journals (Sweden)

    Jean-François eDesaphy

    2012-02-01

    Full Text Available We previously showed that the β-adrenoceptor modulators, clenbuterol and propranolol, directly blocked voltage-gated sodium channels, whereas salbutamol and nadolol did not (Desaphy et al., 2003, suggesting the presence of two hydroxyl groups on the aromatic moiety of the drugs as a molecular requisite for impeding sodium channel block. To verify such an hypothesis, we synthesized five new mexiletine analogues by adding one or two hydroxyl groups to the aryl moiety of the sodium channel blocker and tested these compounds on hNav1.4 channels expressed in HEK293 cells. Concentration-response relationships were constructed using an holding potential of -120 mV at 0.1 Hz (tonic block and 10 Hz (use-dependent block stimulation frequencies. The half-maximum inhibitory concentrations (IC50 were linearly correlated to drug lipophilicity: the less lipophilic the drug, minor was the block. The same compounds were also tested on F1586C and Y1593C hNav1.4 channel mutants, to gain further information on the molecular interactions of mexiletine with its receptor within the sodium channel pore. Alteration of tonic block suggests that the aryl moiety of mexiletine may interact either directly or indirectly with Phe1586 in the closed sodium channel to produce low-affinity binding block, and that this interaction depends on the electrostatic potential of the drug aromatic tail. Alteration of use-dependent block suggests that addition of hydroxyl groups to the aryl moiety may modify high-affinity binding of the drug ammine terminal to Phe1586 through cooperativity between the two pharmacophores, this effect being mainly related to drug lipophilicity. Mutation of Tyr1593 further impaired such cooperativity. In conclusion, these results confirm our former hypothesis showing that the presence of hydroxyl groups to the aryl moiety of mexiletine greatly reduced sodium channel block, and provide molecular insights into the intimate interaction of local anesthetics with

  9. Analysis of the selectivity filter of the voltage-gated sodium channel NavRh

    Institute of Scientific and Technical Information of China (English)

    Xu Zhang; Mengdie Xia; Yang Li; Huihui Liu; Xin Jiang; Wenlin Ren; Jianping Wu

    2013-01-01

    NaChBac is a bacterial voltage-gated sodium (Nav) channel that shows sequence similarity to voltage-gated calcium channels.To understand the ion-permeation mechanism of Nav channels,we combined molecular dynamics simulation,structural biology and electrophysiological approaches to investigate the recently determined structure of NavRh,a marine bacterial NaChBac ortholog.Two Na+ binding sites are identified in the selectivity filter (SF) in our simulations:The extracellular Na+ ion first approaches site 1 constituted by the side groups of Ser181 and Glu183,and then spontaneously arrives at the energetically more favorable site 2 formed by the carbonyi oxygens of Leu179 and Thr178.In contrast,Ca2+ ions are prone to being trapped by Glu183 at site 1,which then blocks the entrance of both Na+ and Ca2+ to the vestibule of the SF.In addition,Na+ permeates through the selective filter in an asymmetrical manner,a feature that resembles that of the mammalian Nav orthologs.The study reported here provides insights into the mechanism of ion selectivity on Na+ over Ca2+ in mammalian Nav channels.

  10. Mechanism of Ion Permeation in Mammalian Voltage-Gated Sodium Channels.

    Directory of Open Access Journals (Sweden)

    Somayeh Mahdavi

    Full Text Available Recent determination of the crystal structures of bacterial voltage-gated sodium (NaV channels have raised hopes that modeling of the mammalian counterparts could soon be achieved. However, there are substantial differences between the pore domains of the bacterial and mammalian NaV channels, which necessitates careful validation of mammalian homology models constructed from the bacterial NaV structures. Such a validated homology model for the NaV1.4 channel was constructed recently using the extensive mutagenesis data available for binding of μ-conotoxins. Here we use this NaV1.4 model to study the ion permeation mechanism in mammalian NaV channels. Linking of the DEKA residues in the selectivity filter with residues in the neighboring domains is found to be important for keeping the permeation pathway open. Molecular dynamics simulations and potential of mean force calculations reveal that there is a binding site for a Na+ ion just inside the DEKA locus, and 1-2 Na+ ions can occupy the vestibule near the EEDD ring. These sites are separated by a low free energy barrier, suggesting that inward conduction occurs when a Na+ ion in the vestibule goes over the free energy barrier and pushes the Na+ ion in the filter to the intracellular cavity, consistent with the classical knock-on mechanism. The NaV1.4 model also provides a good description of the observed Na+/K+ selectivity.

  11. Generalized epilepsy with febrile seizures plus-associated sodium channel beta1 subunit mutations severely reduce beta subunit-mediated modulation of sodium channel function.

    Science.gov (United States)

    Xu, R; Thomas, E A; Gazina, E V; Richards, K L; Quick, M; Wallace, R H; Harkin, L A; Heron, S E; Berkovic, S F; Scheffer, I E; Mulley, J C; Petrou, S

    2007-08-10

    Two novel mutations (R85C and R85H) on the extracellular immunoglobulin-like domain of the sodium channel beta1 subunit have been identified in individuals from two families with generalized epilepsy with febrile seizures plus (GEFS+). The functional consequences of these two mutations were determined by co-expression of the human brain NaV1.2 alpha subunit with wild type or mutant beta1 subunits in human embryonic kidney (HEK)-293T cells. Patch clamp studies confirmed the regulatory role of beta1 in that relative to NaV1.2 alone the NaV1.2+beta1 currents had right-shifted voltage dependence of activation, fast and slow inactivation and reduced use dependence. In addition, the NaV1.2+beta1 current entered fast inactivation slightly faster than NaV1.2 channels alone. The beta1(R85C) subunit appears to be a complete loss of function in that none of the modulating effects of the wild type beta1 were observed when it was co-expressed with NaV1.2. Interestingly, the beta1(R85H) subunit also failed to modulate fast kinetics, however, it shifted the voltage dependence of steady state slow inactivation in the same way as the wild type beta1 subunit. Immunohistochemical studies revealed cell surface expression of the wild type beta1 subunit and undetectable levels of cell surface expression for both mutants. The functional studies suggest association of the beta1(R85H) subunit with the alpha subunit where its influence is limited to modulating steady state slow inactivation. In summary, the mutant beta1 subunits essentially fail to modulate alpha subunits which could increase neuronal excitability and underlie GEFS+ pathogenesis. PMID:17629415

  12. Charged Polymers Transport under Applied Electric Fields in Periodic Channels

    Directory of Open Access Journals (Sweden)

    Sorin Nedelcu

    2013-07-01

    Full Text Available By molecular dynamics simulations, we investigated the transport of charged polymers in applied electric fields in confining environments, which were straight cylinders of uniform or non-uniform diameter. In the simulations, the solvent was modeled explicitly and, also, the counterions and coions of added salt. The electrophoretic velocities of charged chains in relation to electrolyte friction, hydrodynamic effects due to the solvent, and surface friction were calculated. We found that the velocities were higher if counterions were moved away from the polymeric domain, which led to a decrease in hydrodynamic friction. The topology of the surface played a key role in retarding the motion of the polyelectrolyte and, even more so, in the presence of transverse electric fields. The present study showed that a possible way of improving separation resolution is by controlling the motion of counterions or electrolyte friction effects.

  13. Charge and Mass Effects on Low Energy Ion Channeling in Carbon Nanotubes

    Institute of Scientific and Technical Information of China (English)

    LI Yong; ZHENG Li-Ping; ZHANG Wei; XV Zi-Jian; REN Cui-Lan; HUAI Ping; ZHU Zhi-Yuan

    2011-01-01

    @@ Channeling phenomena of He, Ne, Ar and Kr ions at energy (200-5000eV) in single-wall carbon nanotubes (SWCNTs) are investigated by molecular dynamics simulation with analytical potentials.The critical angles for the particles to be channeled in an SWCNT are analyzed.In the incident energy range of 200-5000 eV, it is found that the ion energy dependence of the critical angle obeys an improved Lindhard equation which is closely related to the ratio of nuclear charge number to atomic mass Z/M.The critical angle for different types of ions channeling in SWCNTs is determined by both the atomic nuclear charge and mass.%Channeling phenomena of He, Ne, Ar and Kr ions at energy (200-5000eV) in single-wall carbon nanotubes (SWCNTs) are investigated by molecular dynamics simulation with analytical potentials. The critical angles for the particles to be channeled in an SWCNT are analyzed. In the incident energy range of 200-5000eV, it is found that the ion energy dependence of the critical angle obeys an improved Lindhard equation which is closely related to the ratio of nuclear charge number to atomic mass Z/M. The critical angle for different types of ions channeling in SWCNTs is determined by both the atomic nuclear charge and mass.

  14. Expression patterns, mutation detection and RNA interference of Rhopalosiphum padi voltage-gated sodium channel genes

    Science.gov (United States)

    Zuo, Yayun; Peng, Xiong; Wang, Kang; Lin, Fangfei; Li, Yuting; Chen, Maohua

    2016-07-01

    The voltage-gated sodium channel (VGSC) is the target of sodium-channel-blocking insecticides. Traditionally, animals were thought to have only one VGSC gene comprising a α-subunit with four homologous domains (DI–DIV). The present study showed that Rhopalosiphum padi, an economically important crop pest, owned a unique heterodimeric VGSC (H1 and H2 subunits) encoded by two genes (Rpvgsc1 and Rpvgsc2), which is unusual in insects and other animals. The open reading frame (ORF) of Rpvgsc1 consisted 1150 amino acids, and the ORF of Rpvgsc2 had 957 amino acids. Rpvgsc1 showed 64.1% amino acid identity to DI–DII of Drosophila melanogaster VGSC and Rpvgsc2 showed 64.0% amino acid identity to DIII–DIV of D. melanogaster VGSC. A M918L mutation previously reported in pyrethroids-resistant strains of other insects was found in the IIS4-S6 region of R. padi field sample. The two R. padi VGSC genes were expressed at all developmental stages and showed similar expression patterns after treatment with beta-cypermethrin. Knockdown of Rpvgsc1 or Rpvgsc2 caused significant reduction in mortality rate of R. padi after exposure to beta-cypermethrin. These findings suggest that the two R. padi VGSC genes are both functional genes.

  15. Expression patterns, mutation detection and RNA interference of Rhopalosiphum padi voltage-gated sodium channel genes

    Science.gov (United States)

    Zuo, Yayun; Peng, Xiong; Wang, Kang; Lin, Fangfei; Li, Yuting; Chen, Maohua

    2016-07-01

    The voltage-gated sodium channel (VGSC) is the target of sodium-channel-blocking insecticides. Traditionally, animals were thought to have only one VGSC gene comprising a α-subunit with four homologous domains (DI-DIV). The present study showed that Rhopalosiphum padi, an economically important crop pest, owned a unique heterodimeric VGSC (H1 and H2 subunits) encoded by two genes (Rpvgsc1 and Rpvgsc2), which is unusual in insects and other animals. The open reading frame (ORF) of Rpvgsc1 consisted 1150 amino acids, and the ORF of Rpvgsc2 had 957 amino acids. Rpvgsc1 showed 64.1% amino acid identity to DI-DII of Drosophila melanogaster VGSC and Rpvgsc2 showed 64.0% amino acid identity to DIII-DIV of D. melanogaster VGSC. A M918L mutation previously reported in pyrethroids-resistant strains of other insects was found in the IIS4-S6 region of R. padi field sample. The two R. padi VGSC genes were expressed at all developmental stages and showed similar expression patterns after treatment with beta-cypermethrin. Knockdown of Rpvgsc1 or Rpvgsc2 caused significant reduction in mortality rate of R. padi after exposure to beta-cypermethrin. These findings suggest that the two R. padi VGSC genes are both functional genes.

  16. Distinct functional defect of three novel Brugada syndrome related cardiac sodium channel mutations

    Directory of Open Access Journals (Sweden)

    Juang Jyh-Ming

    2009-02-01

    Full Text Available Abstract The Brugada syndrome is characterized by ST segment elevation in the right precodial leads V1-V3 on surface ECG accompanied by episodes of ventricular fibrillation causing syncope or even sudden death. The molecular and cellular mechanisms that lead to Brugada syndrome are not yet completely understood. However, SCN5A is the most well known responsible gene that causes Brugada syndrome. Until now, more than a hundred mutations in SCN5A responsible for Brugada syndrome have been described. Functional studies of some of the mutations have been performed and show that a reduction of human cardiac sodium current accounts for the pathogenesis of Brugada syndrome. Here we reported three novel SCN5A mutations identified in patients with Brugada syndrome in Taiwan (p.I848fs, p.R965C, and p.1876insM. Their electrophysiological properties were altered by patch clamp analysis. The p.I848fs mutant generated no sodium current. The p.R965C and p.1876insM mutants produced channels with steady state inactivation shifted to a more negative potential (9.4 mV and 8.5 mV respectively, and slower recovery from inactivation. Besides, the steady state activation of p.1876insM was altered and was shifted to a more positive potential (7.69 mV. In conclusion, the SCN5A channel defect related to Brugada syndrome might be diverse but all resulted in a decrease of sodium current.

  17. State-Dependent Inhibition of Sodium Channels by Local Anesthetics: A 40-Year Evolution.

    Science.gov (United States)

    Wang, G-K; Strichartz, G R

    2012-04-01

    Knowledge about the mechanism of impulse blockade by local anesthetics has evolved over the past four decades, from the realization that Na(+) channels were inhibited to affect the impulse blockade to an identification of the amino acid residues within the Na(+) channel that bind the local anesthetic molecule. Within this period appreciation has grown of the state-dependent nature of channel inhibition, with rapid binding and unbinding at relatively high affinity to the open state, and weaker binding to the closed resting state. Slow binding of high affinity for the inactivated state accounts for the salutary therapeutic as well as the toxic actions of diverse class I anti-arrhythmic agents, but may have little importance for impulse blockade, which requires concentrations high enough to block the resting state. At the molecular level, residues on the S6 transmembrane segments in three of the homologous domains of the channel appear to contribute to the binding of local anesthetics, with some contribution also from parts of the selectivity filter. Binding to the inactivated state, and perhaps the open state, involves some residues that are not identical to those that bind these drugs in the resting state, suggesting spatial flexibility in the "binding site". Questions remaining include the mechanism that links local anesthetic binding with the inhibition of gating charge movements, and the molecular nature of the theoretical "hydrophobic pathway" that may be critical for determining the recovery rates from blockade of closed channels, and thus account for both therapeutic and cardiotoxic actions. PMID:23710324

  18. Epithelial Sodium Channel-Mediated Sodium Transport Is Not Dependent on the Membrane-Bound Serine Protease CAP2/Tmprss4.

    Directory of Open Access Journals (Sweden)

    Anna Keppner

    Full Text Available The membrane-bound serine protease CAP2/Tmprss4 has been previously identified in vitro as a positive regulator of the epithelial sodium channel (ENaC. To study its in vivo implication in ENaC-mediated sodium absorption, we generated a knockout mouse model for CAP2/Tmprss4. Mice deficient in CAP2/Tmprss4 were viable, fertile, and did not show any obvious histological abnormalities. Unexpectedly, when challenged with sodium-deficient diet, these mice did not develop any impairment in renal sodium handling as evidenced by normal plasma and urinary sodium and potassium electrolytes, as well as normal aldosterone levels. Despite minor alterations in ENaC mRNA expression, we found no evidence for altered proteolytic cleavage of ENaC subunits. In consequence, ENaC activity, as monitored by the amiloride-sensitive rectal potential difference (ΔPD, was not altered even under dietary sodium restriction. In summary, ENaC-mediated sodium balance is not affected by lack of CAP2/Tmprss4 expression and thus, does not seem to directly control ENaC expression and activity in vivo.

  19. A sodium channel myotonia due to a novel SCN4A mutation accompanied by acquired autoimmune myasthenia gravis.

    Science.gov (United States)

    Kokunai, Yosuke; Goto, Keigo; Kubota, Tomoya; Fukuoka, Takaaki; Sakoda, Saburo; Ibi, Tohru; Doyu, Manabu; Mochizuki, Hideki; Sahashi, Ko; Takahashi, Masanori P

    2012-06-21

    Mutations of the voltage gated sodium channel gene (SCN4A) are responsible for non-dystrophic myotonia including hyperkalemic periodic paralysis, paramyotonia congenita, and sodium channel myotonia, as well as congenital myasthenic syndrome. In vitro functional analyses have demonstrated the non-dystrophic mutants to show a gain-of-function defect of the channel; a disruption of fast inactivation, an enhancement of activation, or both, while the myasthenic mutation presents a loss-of function defect. This report presents a case of non-dystrophic myotonia that is incidentally accompanied with acquired myasthenia. The patient presented a marked warm-up phenomenon of myotonia but the repeated short exercise test suggested mutations of the sodium channel. The genetic analysis identified a novel mutation, G1292D, of SCN4A. A functional study of the mutant channel revealed marked enhancement of activation and slight impairment of fast inactivation, which should induce muscle hyperexcitability. The effects of the alteration of channel function to the myasthenic symptoms were explored by using stimulation of repetitive depolarization pulses. A use-dependent channel inactivation was reduced in the mutant in comparison to normal channel, thus suggesting an opposing effect to myasthenia. PMID:22617007

  20. Sodium channel Nav1.7 immunoreactivity in painful human dental pulp and burning mouth syndrome

    Directory of Open Access Journals (Sweden)

    Yiangou Yiangos

    2010-06-01

    Full Text Available Abstract Background Voltage gated sodium channels Nav1.7 are involved in nociceptor nerve action potentials and are known to affect pain sensitivity in clinical genetic disorders. Aims and Objectives To study Nav1.7 levels in dental pulpitis pain, an inflammatory condition, and burning mouth syndrome (BMS, considered a neuropathic orofacial pain disorder. Methods Two groups of patients were recruited for this study. One group consisted of patients with dental pulpitis pain (n = 5 and controls (n = 12, and the other patients with BMS (n = 7 and controls (n = 10. BMS patients were diagnosed according to the International Association for the Study of Pain criteria; a pain history was collected, including the visual analogue scale (VAS. Immunohistochemistry with visual intensity and computer image analysis were used to evaluate levels of Nav1.7 in dental pulp tissue samples from the dental pulpitis group, and tongue biopsies from the BMS group. Results There was a significantly increased visual intensity score for Nav1.7 in nerve fibres in the painful dental pulp specimens, compared to controls. Image analysis showed a trend for an increase of the Nav1.7 immunoreactive % area in the painful pulp group, but this was not statistically significant. When expressed as a ratio of the neurofilament % area, there was a strong trend for an increase of Nav1.7 in the painful pulp group. Nav1.7 immunoreactive fibres were seen in abundance in the sub-mucosal layer of tongue biopsies, with no significant difference between BMS and controls. Conclusion Nav1.7 sodium channel may play a significant role in inflammatory dental pain. Clinical trials with selective Nav1.7 channel blockers should prioritise dental pulp pain rather than BMS.

  1. Isovector coupling channel and central properties of the charge density distribution in heavy spherical nuclei

    Indian Academy of Sciences (India)

    S Haddad

    2010-09-01

    The influence of the isovector coupling channel on the central depression parameter and the central value of the charge density distribution in heavy spherical nuclei was studied. The isovector coupling channel leads to about 50% increase of the central depression parameter, and weakens the dependency of both central depression parameter and central density on the asymmetry, impressively contributing to the semibubble form of the charge density distribution in heavy nuclei, and increasing the probability of larger nuclei with higher proton numbers and higher neutron-to-proton ratios stable.

  2. A 128-channel picoammeter system and its application on charged particle beam current distribution measurements

    Science.gov (United States)

    Yu, Deyang; Liu, Junliang; Xue, Yingli; Zhang, Mingwu; Cai, Xiaohong; Hu, Jianjun; Dong, Jinmei; Li, Xin

    2015-11-01

    A 128-channel picoammeter system is constructed based on instrumentation amplifiers. Taking advantage of a high electric potential and narrow bandwidth in DC energetic charged beam measurements, a current resolution better than 5 fA can be achieved. Two sets of 128-channel strip electrodes are implemented on printed circuit boards and are employed for ion and electron beam current distribution measurements. Tests with 60 keV O3+ ions and 2 keV electrons show that it can provide exact boundaries when a positive charged particle beam current distribution is measured.

  3. Ion slowing down and charge exchange at small impact parameters selected by channeling: superdensity effects

    OpenAIRE

    L'Hoir, A.; Adoui, A.; Barrué, F.; Billebaud, A.; Bosch, F.; Bräuning-Demian, A.; Bräuning, H.; Cassimi, A.; Chevallier, M.; C. Cohen; Dauvergne, D; Demonchy, C.E.; Giot, L.; Kirsch, R.; Gumberidze, A

    2005-01-01

    In two experiments performed with 20-30 MeV/u highly charged heavy ions (Pb56+, U91+) channeled through thin silicon crystals, we observed the original features of superdensity, associated to the glancing collisions with atomic rows undergone by part of the incident projectiles. In particular the very high collision rate yields a quite specific charge exchange regime, that leads to a higher ionization probability than in random conditions. X-ray measurements show that electrons captured in ou...

  4. Role of the epithelial sodium channel in salt-sensitive hypertension

    Institute of Scientific and Technical Information of China (English)

    Yan SUN; Jia-ning ZHANG; Dan ZHAO; Qiu-shi WANG; Yu-chun GU; He-ping MA; Zhi-ren ZHANG

    2011-01-01

    The epithelial sodium channel (ENaC) is a heteromeric channel composed of three similar but distinct subunits, a, β and Y. This channel is an end-effector in the rennin-angiotensin-aldosterone system and resides in the apical plasma membrane of the renal cortical collecting ducts, where reabsorption of Na+ through ENaC is the final renal adjustment step for Na+ balance. Because of its regulation and function, the ENaC plays a critical role in modulating the homeostasis of Na+ and thus chronic blood pressure. The development of most forms of hypertension requires an increase in Na+ and water retention. The role of ENaC in developing high blood pressure is exemplified in the gain-of-function mutations in ENaC that cause Liddle's syndrome, a severe but rare form of inheritable hypertension.The evidence obtained from studies using animal models and in human patients indicates that improper Na+ retention by the kidney elevates blood pressure and induces salt-sensitive hypertension.

  5. Negative-dominance phenomenon with genetic variants of the cardiac sodium channel Nav1.5.

    Science.gov (United States)

    Sottas, Valentin; Abriel, Hugues

    2016-07-01

    During the past two decades, many pathological genetic variants in SCN5A, the gene encoding the pore-forming subunit of the cardiac (monomeric) sodium channel Na(v)1.5, have been described. Negative dominance is a classical genetic concept involving a "poison" mutant peptide that negatively interferes with the co-expressed wild-type protein, thus reducing its cellular function. This phenomenon has been described for genetic variants of multimeric K(+) channels, which mechanisms are well understood. Unexpectedly, several pathologic SCN5A variants that are linked to Brugada syndrome also demonstrate such a dominant-negative (DN) effect. The molecular determinants of these observations, however, are not yet elucidated. This review article summarizes recent findings that describe the mechanisms underlying the DN phenomenon of genetic variants of K(+), Ca(2+), Cl(-) and Na(+) channels, and in particular Brugada syndrome variants of Na(v)1.5. This article is part of a Special Issue entitled: Cardiomyocyte Biology: Integration of Developmental and Environmental Cues in the Heart edited by Marcus Schaub and Hughes Abriel.

  6. A novel mutation in the sodium channel α1 subunit gene in a child with Dravet syndrome in Turkey

    Institute of Scientific and Technical Information of China (English)

    Mutluay Arslan; Ulu(c) Yi(s); Hande (C)a(g)layan; R1dvan Akin

    2013-01-01

    Dravet syndrome is a rare epileptic encephalopathy characterized by frequent seizures beginning in the first year of life and behavioral disorders. Mutations in the sodium channel α1 subunit gene are the main cause of this disease. We report two patients with refractory seizures and psychomotor retardation in whom the final diagnosis was Dravet syndrome with confirmed mutations in the sodium channel α1 subunit gene. The mutation identified in the second patient was a novel frame shift mutation, which resulted from the deletion of five nucleotides in exon 24.

  7. Charge Fluctuations and Boundary Conditions of Biological Ion Channels: Effect on the Ionic Transition Rate

    Science.gov (United States)

    Tindjong, R.; Luchinsky, D. G.; McClintock, P. V. E.; Kaufman, I.; Eisenberg, R. S.

    2009-04-01

    A self-consistent solution is derived for the Poisson-Nernst-Planck (PNP) equation, valid both inside a biological ion channel and in the adjacent bulk fluid. An iterative procedure is used to match the two solutions together at the channel mouth. Charge fluctuations at the mouth are modeled as shot noise flipping the height of the potential barrier at the selectivity site. The resultant estimates of the conductivity of the ion channel are in good agreement with Gramicidin experimental measurements and they reproduce the observed current saturation with increasing concentration.

  8. Different pH-sensitivity patterns of 30 sodium channel inhibitors suggest chemically different pools along the access pathway.

    Directory of Open Access Journals (Sweden)

    Alexandra eLazar

    2015-09-01

    Full Text Available The major drug binding site of sodium channels is inaccessible from the extracellular side, drug molecules can only access it either from the membrane phase, or from the intracellular aqueous phase. For this reason, ligand-membrane interactions are as important determinants of inhibitor properties, as ligand-protein interactions. One way to probe this is to modify the pH of the extracellular fluid, which alters the ratio of charged vs. uncharged forms of some compounds, thereby changing their interaction with the membrane. In this electrophysiology study we used three different pH values: 6.0, 7.3 and 8.6 to test the significance of the protonation-deprotonation equilibrium in drug access and affinity. We investigated drugs of several different indications: carbamazepine, lamotrigine, phenytoin, lidocaine, bupivacaine, mexiletine, flecainide, ranolazine, riluzole, memantine, ritanserin, tolperisone, silperisone, ambroxol, haloperidol, chlorpromazine, clozapine, fluoxetine, sertraline, paroxetine, amitriptyline, imipramine, desipramine, maprotiline, nisoxetine, mianserin, mirtazapine, venlafaxine, nefazodone and trazodone. We recorded the pH-dependence of potency, reversibility, as well as onset/offset kinetics. As expected, we observed a strong correlation between the acidic dissociation constant (pKa of drugs and the pH-dependence of their potency. Unexpectedly, however, the pH-dependence of reversibility or kinetics showed diverse patterns, not simple correlation. Our data are best explained by a model where drug molecules can be trapped in at least two chemically different environments: A hydrophilic trap (which may be the aqueous cavity within the inner vestibule, which favors polar and less lipophilic compounds, and a lipophilic trap (which may be the membrane phase itself, and/or lipophilic binding sites on the channel. Rescue from the hydrophilic and lipophilic traps can be promoted by alkalic and acidic extracellular pH, respectively.

  9. Charged Higgs Search via $AW^\\pm/HW^\\pm$ Channel

    CERN Document Server

    Coleppa, Baradhwaj; Su, Shufang

    2014-01-01

    Models of electroweak symmetry breaking with extended Higgs sectors are theoretically well motivated. In this study, we focus on models with a low energy spectrum containing a pair of charged scalars $H^\\pm$, as well as a light scalar H and/or a pseudoscalar A. We study the $H^\\pm tb$ associated production with $H^\\pm \\to AW/HW$, which could reach sizable branching fractions in certain parameter regions. With detailed collider analysis, we obtain the exclusion bounds as well as discovery reach at the 14 TeV LHC for the process $pp \\to H^\\pm tb \\to AWtb/HWtb \\to \\tau\\tau bbWW, bbbbWW$. We find that for a daughter particle mass of 50 GeV, the 95% C.L. exclusion reach in $\\sigma$xBR varies from about 70 fb to 25 fb, for $m_{H^\\pm}$ ranging from 150 GeV to 500 GeV with 300 fb$^{-1}$ integrated luminosity in the $\\tau\\tau$ mode. We further interpret these bounds in the context of Type II Two Higgs Doublet Model. We find that large regions of parameter space in $\\tan\\beta$ versus $\\sin(\\beta-\\alpha)$ can be covered...

  10. Proteolytic activation of the epithelial sodium channel ENaC in preeclampsia examined with urinary exosomes

    DEFF Research Database (Denmark)

    Nielsen, Maria Ravn; Rytz, Mie; Frederiksen-Møller, Britta;

    2015-01-01

    OBJECTIVES: Increased activity of the epithelial sodium channel (ENaC) in the kidneys may explain the coupling between proteinuria, edema, suppressed aldosterone and hypertension in preeclampsia. Preeclamptic women excrete plasminogen-plasmin in urine. In vitro, plasmin increases the activity...... as a positive control for the presence of collecting duct membrane. RESULTS: Urine plasmin-plasminogen/creatinine ratio was increased in the preeclampsia group (p... pregnancy and preeclampsia CONCLUSIONS: It is possible to examine collecting duct transport proteins in urine exosome from pregnant women including γ-ENaC, 2) Urine exosome fraction displays a variable pattern of γ-ENaC signal with a predominance of cleaved forms in both normal and preeclamptic women...

  11. Multiple mutations and mutation combinations in the sodium channel of permethrin resistant mosquitoes, Culex quinquefasciatus

    Science.gov (United States)

    Li, Ting; Zhang, Lee; Reid, William R.; Xu, Qiang; Dong, Ke; Liu, Nannan

    2012-10-01

    A previous study identified 3 nonsynonymous and 6 synonymous mutations in the entire mosquito sodium channel of Culex quinquefasciatus, the prevalence of which were strongly correlated with levels of resistance and increased dramatically following insecticide selection. However, it is unclear whether this is unique to this specific resistant population or is a common mechanism in field mosquito populations in response to insecticide pressure. The current study therefore further characterized these mutations and their combinations in other field and permethrin selected Culex mosquitoes, finding that the co-existence of all 9 mutations was indeed correlated with the high levels of permethrin resistance in mosquitoes. Comparison of mutation combinations revealed several common mutation combinations presented across different field and permethrin selected populations in response to high levels of insecticide resistance, demonstrating that the co-existence of multiple mutations is a common event in response to insecticide resistance across different Cx. quinquefasciatus mosquito populations.

  12. Aberrant epilepsy-associated mutant Nav1.6 sodium channel activity can be targeted with cannabidiol.

    Science.gov (United States)

    Patel, Reesha R; Barbosa, Cindy; Brustovetsky, Tatiana; Brustovetsky, Nickolay; Cummins, Theodore R

    2016-08-01

    Mutations in brain isoforms of voltage-gated sodium channels have been identified in patients with distinct epileptic phenotypes. Clinically, these patients often do not respond well to classic anti-epileptics and many remain refractory to treatment. Exogenous as well as endogenous cannabinoids have been shown to target voltage-gated sodium channels and cannabidiol has recently received attention for its potential efficacy in the treatment of childhood epilepsies. In this study, we further investigated the ability of cannabinoids to modulate sodium currents from wild-type and epilepsy-associated mutant voltage-gated sodium channels. We first determined the biophysical consequences of epilepsy-associated missense mutations in both Nav1.1 (arginine 1648 to histidine and asparagine 1788 to lysine) and Nav1.6 (asparagine 1768 to aspartic acid and leucine 1331 to valine) by obtaining whole-cell patch clamp recordings in human embryonic kidney 293T cells with 200 μM Navβ4 peptide in the pipette solution to induce resurgent sodium currents. Resurgent sodium current is an atypical near threshold current predicted to increase neuronal excitability and has been implicated in multiple disorders of excitability. We found that both mutations in Nav1.6 dramatically increased resurgent currents while mutations in Nav1.1 did not. We then examined the effects of anandamide and cannabidiol on peak transient and resurgent currents from wild-type and mutant channels. Interestingly, we found that cannabidiol can preferentially target resurgent sodium currents over peak transient currents generated by wild-type Nav1.6 as well as the aberrant resurgent and persistent current generated by Nav1.6 mutant channels. To further validate our findings, we examined the effects of cannabidiol on endogenous sodium currents from striatal neurons, and similarly we found an inhibition of resurgent and persistent current by cannabidiol. Moreover, current clamp recordings show that cannabidiol reduces

  13. Hydrogen Sulfide Prevents Advanced Glycation End-Products Induced Activation of the Epithelial Sodium Channel

    Directory of Open Access Journals (Sweden)

    Qiushi Wang

    2015-01-01

    Full Text Available Advanced glycation end-products (AGEs are complex and heterogeneous compounds implicated in diabetes. Sodium reabsorption through the epithelial sodium channel (ENaC at the distal nephron plays an important role in diabetic hypertension. Here, we report that H2S antagonizes AGEs-induced ENaC activation in A6 cells. ENaC open probability (PO in A6 cells was significantly increased by exogenous AGEs and that this AGEs-induced ENaC activity was abolished by NaHS (a donor of H2S and TEMPOL. Incubating A6 cells with the catalase inhibitor 3-aminotriazole (3-AT mimicked the effects of AGEs on ENaC activity, but did not induce any additive effect. We found that the expression levels of catalase were significantly reduced by AGEs and both AGEs and 3-AT facilitated ROS uptake in A6 cells, which were significantly inhibited by NaHS. The specific PTEN and PI3K inhibitors, BPV(pic  and LY294002, influence ENaC activity in AGEs-pretreated A6 cells. Moreover, after removal of AGEs from AGEs-pretreated A6 cells for 72 hours, ENaC PO remained at a high level, suggesting that an AGEs-related “metabolic memory” may be involved in sodium homeostasis. Our data, for the first time, show that H2S prevents AGEs-induced ENaC activation by targeting the ROS/PI3K/PTEN pathway.

  14. Parkinson's disease-like forelimb akinesia induced by BmK I, a sodium channel modulator.

    Science.gov (United States)

    Zhu, Hongyan; Wang, Ziyi; Jin, Jiahui; Pei, Xiao; Zhao, Yuxiao; Wu, Hao; Lin, Weide; Tao, Jie; Ji, Yonghua

    2016-07-15

    Parkinson's disease (PD) is a neurodegenerative disorder and characterized by motor disabilities which are mostly linked with high levels of synchronous oscillations in the basal ganglia neurons. Voltage-gated sodium channels (VGSCs) play a vital role in the abnormal electrical activity of neurons in the globus pallidus (GP) and the subthalamic nucleus (STN) in PD. BmK I, a α-like toxin purified from the Chinese scorpion Buthus martensi Karsch, has been identified a site-3-specific modulator of VGSCs. The present study shows that forelimb akinesia can be induced by the injection of BmK I into the globus pallidus (GP) in rats. In addition, BmK I cannot produce neuronal damage in vivo and in vitro at 24h after treatment, indicating that the forelimb akinesia does not result from neuronal damage. Electrophysiological studies further revealed that the inactivated Na(+) currents were showed to be more vulnerably modulated by BmK I than the activated Na(+) currents in human neuron-like SHSY5Y cells. Furthermore, the modulation of BmK I on inactivation was preferentially attributed to fast inactivation rather than slow inactivation. Therefore, the PD-like forelimb akinesia may result from the modulation of sodium channels in neuron by BmK I. These findings not only suggest that BmK I may be an effective and novel molecule for the study of pathogenesis in PD but also support the idea that VGSCs play a crucial role in the motor disabilities in PD. PMID:27108049

  15. Block of Brain Sodium Channels by Peptide Mimetics of the Isoleucine, Phenylalanine, and Methionine (IFM) Motif from the Inactivation Gate

    OpenAIRE

    Eaholtz, Galen; Colvin, Anita; Leonard, Daniele; Taylor, Charles(8 Cherryl House, Seymour Gardens, Sutton Coldfield, West Midlands, B74 4ST, U.K.); Catterall, William A.

    1999-01-01

    Inactivation of sodium channels is thought to be mediated by an inactivation gate formed by the intracellular loop connecting domains III and IV. A hydrophobic motif containing the amino acid sequence isoleucine, phenylalanine, and methionine (IFM) is required for the inactivation process. Peptides containing the IFM motif, when applied to the cytoplasmic side of these channels, produce two types of block: fast block, which resembles the inactivation process, and slow, use-dependent block sti...

  16. Modulation of the epithelial sodium channel (ENaC by bacterial metalloproteases and protease inhibitors.

    Directory of Open Access Journals (Sweden)

    Michael B Butterworth

    Full Text Available The serralysin family of metalloproteases is associated with the virulence of multiple gram-negative human pathogens, including Pseudomonas aeruginosa and Serratia marcescens. The serralysin proteases share highly conserved catalytic domains and show evolutionary similarity to the mammalian matrix metalloproteases. Our previous studies demonstrated that alkaline protease (AP from Pseudomonas aeruginosa is capable of activating the epithelial sodium channel (ENaC, leading to an increase in sodium absorption in airway epithelia. The serralysin proteases are often co-expressed with endogenous, intracellular or periplasmic inhibitors, which putatively protect the bacterium from unwanted or unregulated protease activities. To evaluate the potential use of these small protein inhibitors in regulating the serralysin induced activation of ENaC, proteases from Pseudomonas aeruginosa and Serratia marcescens were purified for characterization along with a high affinity inhibitor from Pseudomonas. Both proteases showed activity against in vitro substrates and could be blocked by near stoichiometric concentrations of the inhibitor. In addition, both proteases were capable of activating ENaC when added to the apical surfaces of multiple epithelial cells with similar slow activation kinetics. The high-affinity periplasmic inhibitor from Pseudomonas effectively blocked this activation. These data suggest that multiple metalloproteases are capable of activating ENaC. Further, the endogenous, periplasmic bacterial inhibitors may be useful for modulating the downstream effects of the serralysin virulence factors under physiological conditions.

  17. Modulation of the epithelial sodium channel (ENaC) by bacterial metalloproteases and protease inhibitors.

    Science.gov (United States)

    Butterworth, Michael B; Zhang, Liang; Liu, Xiaoning; Shanks, Robert M; Thibodeau, Patrick H

    2014-01-01

    The serralysin family of metalloproteases is associated with the virulence of multiple gram-negative human pathogens, including Pseudomonas aeruginosa and Serratia marcescens. The serralysin proteases share highly conserved catalytic domains and show evolutionary similarity to the mammalian matrix metalloproteases. Our previous studies demonstrated that alkaline protease (AP) from Pseudomonas aeruginosa is capable of activating the epithelial sodium channel (ENaC), leading to an increase in sodium absorption in airway epithelia. The serralysin proteases are often co-expressed with endogenous, intracellular or periplasmic inhibitors, which putatively protect the bacterium from unwanted or unregulated protease activities. To evaluate the potential use of these small protein inhibitors in regulating the serralysin induced activation of ENaC, proteases from Pseudomonas aeruginosa and Serratia marcescens were purified for characterization along with a high affinity inhibitor from Pseudomonas. Both proteases showed activity against in vitro substrates and could be blocked by near stoichiometric concentrations of the inhibitor. In addition, both proteases were capable of activating ENaC when added to the apical surfaces of multiple epithelial cells with similar slow activation kinetics. The high-affinity periplasmic inhibitor from Pseudomonas effectively blocked this activation. These data suggest that multiple metalloproteases are capable of activating ENaC. Further, the endogenous, periplasmic bacterial inhibitors may be useful for modulating the downstream effects of the serralysin virulence factors under physiological conditions. PMID:24963801

  18. Effect of orphanin FQ and morphine on sodium channel current in somatosensory area of rat cerebral cortex

    Institute of Scientific and Technical Information of China (English)

    Lei Yang; Yurong Li; Shuwei Jia; Yunhong Zhang; Lanwei Cui; Lihui Qu

    2007-01-01

    BACKGROUND: Some experiments have demonstrated that injecting orphanin FQ (OFQ) into lateral ventricle, which can obviously decrease the pain threshold. It is indicated that OFQ is an anti-opiate substance. However, whether OFQ has effects on sensory neuron ion channel in cerebral cortex needs to be further studied.OBJECTIVE: To investigate the effects of OFQ, morphine or their combination on sodium channel current of somatosensory neurons in rat cerebral cortex.DESIGN: Repeated measurement trial.SETTING: Department of Physiology, Harbin Medical University.MATERIALS: Fifty healthy Wistar rats, aged 12-16 days, of either gender, were provided by the Experimental Animal Center, Second Hospital Affiliated to Harbin Medical University. OFQ was purchased from Sigma-Aldrich Company, and morphine was provided by the Shenyang First Pharmaceutical Factory.PC2C patch clamp amplifier and LabmasterTLlwere purchased from Yibo Life Science Instrument Co.,Ltd.of Huazhong University of Science and Techgnology.METHODS: This experiment was carried out in the Department of Physiology (provincial laboratory),Harbin Medical University between January 2005 and May 2006. Cortical neurons were acutely isolated from rats, and prepared into cell suspension following culture. ①Sodium channel current of somatosensory neurons in rat cerebral cortex was recorded before and after administration by whole-cell Patch clamptechnique after 50 nmol/L OFQ being added to extracellular fluid.②The amplitude of sodium channel current of somatosensory neurons in rat cerebral cortex was recorded before and after administration by the same method after 20 I mol/L morphine being added to extracellular fluid, and then the change of sodium channel current was recorded after 50 nmol/L OFQ being added.MAIN OUTCOME MEASURES: The amplitude of sodium channel current of somatosensory neurons in rat cerebral cortex following the administration of OFQ, morphine separately or their combination

  19. Contributions of counter-charge in a potassium channel voltage-sensor domain

    DEFF Research Database (Denmark)

    Pless, Stephan Alexander; Galpin, Jason D; Niciforovic, Ana P;

    2011-01-01

    in transmembrane segments S2 and S3, namely Glu293 and Asp316 in Shaker potassium channels, has little functional effect on conductance-voltage relationships, although Glu293 appears to catalyze S4 movement. Our results suggest that neither Glu293 nor Asp316 engages in electrostatic state-dependent charge...

  20. Charges in the cytoplasmic pore control intrinsic inward rectification and single-channel properties in Kir1.1 and Kir2.1 channels.

    Science.gov (United States)

    Chang, Hsueh-Kai; Yeh, Shih-Hao; Shieh, Ru-Chi

    2007-02-01

    An E224G mutation of the Kir2.1 channel generates intrinsic inward rectification and single-channel fluctuations in the absence of intracellular blockers. In this study, we showed that positively charged residues H226, R228 and R260, near site 224, regulated the intrinsic inward rectification and single-channel properties of the E224G mutant. By carrying out systematic mutations, we found that the charge effect on the intrinsic inward rectification and single-channel conductance is consistent with a long-range electrostatic mechanism. A Kir1.1 channel where the site equivalent to E224 in the Kir2.1 channel is a glycine residue does not show inward rectification or single-channel fluctuations. The G223K and N259R mutations of the Kir1.1 channel induced intrinsic inward rectification and reduced the single-channel conductance but did not generate large open-channel fluctuations. Substituting the cytoplasmic pore of the E224G mutant into the Kir1.1 channel induced open-channel fluctuations and intrinsic inward rectification. The single-channel conductance of the E224G mutant showed inward rectification. Also, a voltage-dependent gating mechanism decreased open probability during depolarization and contributed to the intrinsic inward rectification in the E224G mutant. In addition to an electrostatic effect, a close interaction of K(+) with channel pore may be required for generating open-channel fluctuations in the E224G mutant.

  1. Contributions of Counter-Charge in a Potassium Channel Voltage-Sensor Domain

    Science.gov (United States)

    Pless, Stephan A.; Galpin, Jason D.; Niciforovic, Ana P.; Ahern, Christopher A.

    2016-01-01

    Voltage-sensor domains couple membrane potential to conformational changes in voltage-gated ion channels and phosphatases. Highly co-evolved acidic and aromatic side-chains assist the transfer of cationic side-chains across the transmembrane electric field during voltage-sensing. We investigated the functional contribution of negative electrostatic potentials from these residues to channel gating and voltage-sensing with unnatural amino acid mutagenesis, electrophysiology, voltage-clamp fluorometry and ab initio calculations. The data show that neutralization of two conserved acidic side-chains in transmembrane segments S2 and S3, Glu293 and Asp316 in Shaker potassium channels, have little functional effect on conductance-voltage relationships, although Glu293 appears to catalyze S4 movement. Our results suggest that neither Glu293 nor Asp316 engages in electrostatic state-dependent charge-charge interactions with S4, likely because they occupy, and possibly help create, a water-filled vestibule. PMID:21785425

  2. Engineering Highly Potent and Selective Microproteins against Nav1.7 Sodium Channel for Treatment of Pain.

    Science.gov (United States)

    Shcherbatko, Anatoly; Rossi, Andrea; Foletti, Davide; Zhu, Guoyun; Bogin, Oren; Galindo Casas, Meritxell; Rickert, Mathias; Hasa-Moreno, Adela; Bartsevich, Victor; Crameri, Andreas; Steiner, Alexander R; Henningsen, Robert; Gill, Avinash; Pons, Jaume; Shelton, David L; Rajpal, Arvind; Strop, Pavel

    2016-07-01

    The prominent role of voltage-gated sodium channel 1.7 (Nav1.7) in nociception was revealed by remarkable human clinical and genetic evidence. Development of potent and subtype-selective inhibitors of this ion channel is crucial for obtaining therapeutically useful analgesic compounds. Microproteins isolated from animal venoms have been identified as promising therapeutic leads for ion channels, because they naturally evolved to be potent ion channel blockers. Here, we report the engineering of highly potent and selective inhibitors of the Nav1.7 channel based on tarantula ceratotoxin-1 (CcoTx1). We utilized a combination of directed evolution, saturation mutagenesis, chemical modification, and rational drug design to obtain higher potency and selectivity to the Nav1.7 channel. The resulting microproteins are highly potent (IC50 to Nav1.7 of 2.5 nm) and selective. We achieved 80- and 20-fold selectivity over the closely related Nav1.2 and Nav1.6 channels, respectively, and the IC50 on skeletal (Nav1.4) and cardiac (Nav1.5) sodium channels is above 3000 nm The lead molecules have the potential for future clinical development as novel therapeutics in the treatment of pain. PMID:27129258

  3. The N-terminal domain allosterically regulates cleavage and activation of the epithelial sodium channel.

    Science.gov (United States)

    Kota, Pradeep; Buchner, Ginka; Chakraborty, Hirak; Dang, Yan L; He, Hong; Garcia, Guilherme J M; Kubelka, Jan; Gentzsch, Martina; Stutts, M Jackson; Dokholyan, Nikolay V

    2014-08-15

    The epithelial sodium channel (ENaC) is activated upon endoproteolytic cleavage of specific segments in the extracellular domains of the α- and γ-subunits. Cleavage is accomplished by intracellular proteases prior to membrane insertion and by surface-expressed or extracellular soluble proteases once ENaC resides at the cell surface. These cleavage events are partially regulated by intracellular signaling through an unknown allosteric mechanism. Here, using a combination of computational and experimental techniques, we show that the intracellular N terminus of γ-ENaC undergoes secondary structural transitions upon interaction with phosphoinositides. From ab initio folding simulations of the N termini in the presence and absence of phosphatidylinositol 4,5-bisphosphate (PIP2), we found that PIP2 increases α-helical propensity in the N terminus of γ-ENaC. Electrophysiology and mutation experiments revealed that a highly conserved cluster of lysines in the γ-ENaC N terminus regulates accessibility of extracellular cleavage sites in γ-ENaC. We also show that conditions that decrease PIP2 or enhance ubiquitination sharply limit access of the γ-ENaC extracellular domain to proteases. Further, the efficiency of allosteric control of ENaC proteolysis is dependent on Tyr(370) in γ-ENaC. Our findings provide an allosteric mechanism for ENaC activation regulated by the N termini and sheds light on a potential general mechanism of channel and receptor activation.

  4. The N-terminal Domain Allosterically Regulates Cleavage and Activation of the Epithelial Sodium Channel*

    Science.gov (United States)

    Kota, Pradeep; Buchner, Ginka; Chakraborty, Hirak; Dang, Yan L.; He, Hong; Garcia, Guilherme J. M.; Kubelka, Jan; Gentzsch, Martina; Stutts, M. Jackson; Dokholyan, Nikolay V.

    2014-01-01

    The epithelial sodium channel (ENaC) is activated upon endoproteolytic cleavage of specific segments in the extracellular domains of the α- and γ-subunits. Cleavage is accomplished by intracellular proteases prior to membrane insertion and by surface-expressed or extracellular soluble proteases once ENaC resides at the cell surface. These cleavage events are partially regulated by intracellular signaling through an unknown allosteric mechanism. Here, using a combination of computational and experimental techniques, we show that the intracellular N terminus of γ-ENaC undergoes secondary structural transitions upon interaction with phosphoinositides. From ab initio folding simulations of the N termini in the presence and absence of phosphatidylinositol 4,5-bisphosphate (PIP2), we found that PIP2 increases α-helical propensity in the N terminus of γ-ENaC. Electrophysiology and mutation experiments revealed that a highly conserved cluster of lysines in the γ-ENaC N terminus regulates accessibility of extracellular cleavage sites in γ-ENaC. We also show that conditions that decrease PIP2 or enhance ubiquitination sharply limit access of the γ-ENaC extracellular domain to proteases. Further, the efficiency of allosteric control of ENaC proteolysis is dependent on Tyr370 in γ-ENaC. Our findings provide an allosteric mechanism for ENaC activation regulated by the N termini and sheds light on a potential general mechanism of channel and receptor activation. PMID:24973914

  5. De-novo mutations of the sodium channel gene SCN1A in alleged vaccine encephalopathy : a retrospective study

    NARCIS (Netherlands)

    Berkovic, SF; Harkin, L; McMahon, JM; Pelekanos, JT; Zuberi, SM; Wirrell, EC; Gill, DS; Iona, [No Value; Mulley, JC; Scheffer, IE

    2006-01-01

    Background Vaccination, particularly for pertussis, has been implicated as a direct cause of an encephalopathy with refractory seizures and intellectual impairment. We postulated that cases of so-called vaccine encephalopathy could have mutations in the neuronal sodium channel alpha 1 subunit gene (

  6. Possible roles of exceptionally conserved residues around the selectivity filters of sodium and calcium channels.

    Science.gov (United States)

    Tikhonov, Denis B; Zhorov, Boris S

    2011-01-28

    In the absence of x-ray structures of sodium and calcium channels their homology models are used to rationalize experimental data and design new experiments. A challenge is to model the outer-pore region that folds differently from potassium channels. Here we report a new model of the outer-pore region of the NaV1.4 channel, which suggests roles of highly conserved residues around the selectivity filter. The model takes from our previous study (Tikhonov, D. B., and Zhorov, B. S. (2005) Biophys. J. 88, 184-197) the general disposition of the P-helices, selectivity filter residues, and the outer carboxylates, but proposes new intra- and inter-domain contacts that support structural stability of the outer pore. Glycine residues downstream from the selectivity filter are proposed to participate in knob-into-hole contacts with the P-helices and S6s. These contacts explain the adapted tetrodotoxin resistance of snakes that feed on toxic prey through valine substitution of isoleucine in the P-helix of repeat IV. Polar residues five positions upstream from the selectivity filter residues form H-bonds with the ascending-limb backbones. Exceptionally conserved tryptophans are engaged in inter-repeat H-bonds to form a ring whose π-electrons would facilitate passage of ions from the outer carboxylates to the selectivity filter. The outer-pore model of CaV1.2 derived from the NaV1.4 model is also stabilized by the ring of exceptionally conservative tryptophans and H-bonds between the P-helices and ascending limbs. In this model, the exceptionally conserved aspartate downstream from the selectivity-filter glutamate in repeat II facilitates passage of calcium ions to the selectivity-filter ring through the tryptophan ring. Available experimental data are discussed in view of the models.

  7. Calmodulin and calcium differentially regulate the neuronal Nav1.1 voltage-dependent sodium channel

    International Nuclear Information System (INIS)

    Highlights: → Both Ca++-Calmodulin (CaM) and Ca++-free CaM bind to the C-terminal region of Nav1.1. → Ca++ and CaM have both opposite and convergent effects on INav1.1. → Ca++-CaM modulates INav1.1 amplitude. → CaM hyperpolarizes the voltage-dependence of activation, and increases the inactivation rate. → Ca++ alone antagonizes CaM for both effects, and depolarizes the voltage-dependence of inactivation. -- Abstract: Mutations in the neuronal Nav1.1 voltage-gated sodium channel are responsible for mild to severe epileptic syndromes. The ubiquitous calcium sensor calmodulin (CaM) bound to rat brain Nav1.1 and to the human Nav1.1 channel expressed by a stably transfected HEK-293 cell line. The C-terminal region of the channel, as a fusion protein or in the yeast two-hybrid system, interacted with CaM via a consensus C-terminal motif, the IQ domain. Patch clamp experiments on HEK1.1 cells showed that CaM overexpression increased peak current in a calcium-dependent way. CaM had no effect on the voltage-dependence of fast inactivation, and accelerated the inactivation kinetics. Elevating Ca++ depolarized the voltage-dependence of fast inactivation and slowed down the fast inactivation kinetics, and for high concentrations this effect competed with the acceleration induced by CaM alone. Similarly, the depolarizing action of calcium antagonized the hyperpolarizing shift of the voltage-dependence of activation due to CaM overexpression. Fluorescence spectroscopy measurements suggested that Ca++ could bind the Nav1.1 C-terminal region with micromolar affinity.

  8. Molecular Insights into the Local Anesthetic Receptor within Voltage-Gated Sodium Channels Using Hydroxylated Analogs of Mexiletine.

    Science.gov (United States)

    Desaphy, Jean-François; Dipalma, Antonella; Costanza, Teresa; Carbonara, Roberta; Dinardo, Maria Maddalena; Catalano, Alessia; Carocci, Alessia; Lentini, Giovanni; Franchini, Carlo; Camerino, Diana Conte

    2012-01-01

    We previously showed that the β-adrenoceptor modulators, clenbuterol and propranolol, directly blocked voltage-gated sodium channels, whereas salbutamol and nadolol did not (Desaphy et al., 2003), suggesting the presence of two hydroxyl groups on the aromatic moiety of the drugs as a molecular requisite for impeding sodium channel block. To verify such an hypothesis, we synthesized five new mexiletine analogs by adding one or two hydroxyl groups to the aryloxy moiety of the sodium channel blocker and tested these compounds on hNav1.4 channels expressed in HEK293 cells. Concentration-response relationships were constructed using 25-ms-long depolarizing pulses at -30 mV applied from an holding potential of -120 mV at 0.1 Hz (tonic block) and 10 Hz (use-dependent block) stimulation frequencies. The half-maximum inhibitory concentrations (IC(50)) were linearly correlated to drug lipophilicity: the less lipophilic the drug, minor was the block. The same compounds were also tested on F1586C and Y1593C hNav1.4 channel mutants, to gain further information on the molecular interactions of mexiletine with its receptor within the sodium channel pore. In particular, replacement of Phe1586 and Tyr1593 by non-aromatic cysteine residues may help in the understanding of the role of π-π or π-cation interactions in mexiletine binding. Alteration of tonic block suggests that the aryloxy moiety of mexiletine may interact either directly or indirectly with Phe1586 in the closed sodium channel to produce low-affinity binding block, and that this interaction depends on the electrostatic potential of the drug aromatic tail. Alteration of use-dependent block suggests that addition of hydroxyl groups to the aryloxy moiety may modify high-affinity binding of the drug amine terminal to Phe1586 through cooperativity between the two pharmacophores, this effect being mainly related to drug lipophilicity. Mutation of Tyr1593 further impaired such cooperativity. In conclusion, these

  9. Spontaneous and CRH-Induced Excitability and Calcium Signaling in Mice Corticotrophs Involves Sodium, Calcium, and Cation-Conducting Channels.

    Science.gov (United States)

    Zemkova, Hana; Tomić, Melanija; Kucka, Marek; Aguilera, Greti; Stojilkovic, Stanko S

    2016-04-01

    Transgenic mice expressing the tdimer2(12) form of Discosoma red fluorescent protein under control of the proopiomelanocortin gene's regulatory elements are a useful model for studying corticotrophs. Using these mice, we studied the ion channels and mechanisms controlling corticotroph excitability. Corticotrophs were either quiescent or electrically active, with a 22-mV difference in the resting membrane potential (RMP) between the 2 groups. In quiescent cells, CRH depolarized the membrane, leading to initial single spiking and sustained bursting; in active cells, CRH further facilitated or inhibited electrical activity and calcium spiking, depending on the initial activity pattern and CRH concentration. The stimulatory but not inhibitory action of CRH on electrical activity was mimicked by cAMP independently of the presence or absence of arachidonic acid. Removal of bath sodium silenced spiking and hyperpolarized the majority of cells; in contrast, the removal of bath calcium did not affect RMP but reduced CRH-induced depolarization, which abolished bursting electrical activity and decreased the spiking frequency but not the amplitude of single spikes. Corticotrophs with inhibited voltage-gated sodium channels fired calcium-dependent action potentials, whereas cells with inhibited L-type calcium channels fired sodium-dependent spikes; blockade of both channels abolished spiking without affecting the RMP. These results indicate that the background voltage-insensitive sodium conductance influences RMP, the CRH-depolarization current is driven by a cationic conductance, and the interplay between voltage-gated sodium and calcium channels plays a critical role in determining the status and pattern of electrical activity and calcium signaling.

  10. Validated spectrophotometric methods for determination of sodium valproate based on charge transfer complexation reactions

    Science.gov (United States)

    Belal, Tarek S.; El-Kafrawy, Dina S.; Mahrous, Mohamed S.; Abdel-Khalek, Magdi M.; Abo-Gharam, Amira H.

    2016-02-01

    This work presents the development, validation and application of four simple and direct spectrophotometric methods for determination of sodium valproate (VP) through charge transfer complexation reactions. The first method is based on the reaction of the drug with p-chloranilic acid (p-CA) in acetone to give a purple colored product with maximum absorbance at 524 nm. The second method depends on the reaction of VP with dichlone (DC) in dimethylformamide forming a reddish orange product measured at 490 nm. The third method is based upon the interaction of VP and picric acid (PA) in chloroform resulting in the formation of a yellow complex measured at 415 nm. The fourth method involves the formation of a yellow complex peaking at 361 nm upon the reaction of the drug with iodine in chloroform. Experimental conditions affecting the color development were studied and optimized. Stoichiometry of the reactions was determined. The proposed spectrophotometric procedures were effectively validated with respect to linearity, ranges, precision, accuracy, specificity, robustness, detection and quantification limits. Calibration curves of the formed color products with p-CA, DC, PA and iodine showed good linear relationships over the concentration ranges 24-144, 40-200, 2-20 and 1-8 μg/mL respectively. The proposed methods were successfully applied to the assay of sodium valproate in tablets and oral solution dosage forms with good accuracy and precision. Assay results were statistically compared to a reference pharmacopoeial HPLC method where no significant differences were observed between the proposed methods and reference method.

  11. RNAi-mediated knockdown of the voltage gated sodium ion channel TcNav causes mortality in Tribolium castaneum

    Science.gov (United States)

    Abd El Halim, Hesham M.; Alshukri, Baida M. H.; Ahmad, Munawar S.; Nakasu, Erich Y. T.; Awwad, Mohammed H.; Salama, Elham M.; Gatehouse, Angharad M. R.; Edwards, Martin G.

    2016-01-01

    The voltage-gated sodium ion channel (VGSC) belongs to the largest superfamily of ion channels. Since VGSCs play key roles in physiological processes they are major targets for effective insecticides. RNA interference (RNAi) is widely used to analyse gene function, but recently, it has shown potential to contribute to novel strategies for selectively controlling agricultural insect pests. The current study evaluates the delivery of dsRNA targeted to the sodium ion channel paralytic A (TcNav) gene in Tribolium castaneum as a viable means of controlling this insect pest. Delivery of TcNav dsRNA caused severe developmental arrest with larval mortalities up to 73% post injection of dsRNA. Injected larvae showed significant (p insect control. PMID:27411529

  12. An increase in [Ca2+]i activates basolateral chloride channels and inhibits apical sodium channels in frog skin epithelium

    DEFF Research Database (Denmark)

    Brodin, Birger; Rytved, K A; Nielsen, R

    1996-01-01

    The aim of this study was to investigate the mechanisms by which increases in free cytosolic calcium ([Ca2+]i) cause a decrease in macroscopic sodium absorption across principal cells of the frog skin epithelium. [Ca2+]i was measured with fura-2 in an epifluorescence microscope set-up, sodium...

  13. Adaptive evolution of voltage-gated sodium channels: The first 800 million years

    OpenAIRE

    Zakon, Harold H.

    2012-01-01

    Voltage-gated Na+-permeable (Nav) channels form the basis for electrical excitability in animals. Nav channels evolved from Ca2+ channels and were present in the common ancestor of choanoflagellates and animals, although this channel was likely permeable to both Na+ and Ca2+. Thus, like many other neuronal channels and receptors, Nav channels predated neurons. Invertebrates possess two Nav channels (Nav1 and Nav2), whereas vertebrate Nav channels are of the Nav1 family. Approximately 500 Mya ...

  14. Influence of negative surface charge on toxin binding to canine heart Na channels in planar bilayers.

    OpenAIRE

    Ravindran, A; Moczydlowski, E

    1989-01-01

    The presence of negative surface charge near the tetrodotoxin/saxitoxin binding site of canine heart Na channels was revealed by analysis of the kinetics of toxin block of single batrachotoxin-activated Na channels in planar bilayers as a function of [NaCl]. The voltage-dependence of toxin binding and the toxin dissociation rate are nearly constant as [NaCl] is varied from 0.05 to 3 M. In contrast, the association rate constant of the toxins is inversely dependent on [NaCl], with the rate for...

  15. An Experimental Review of Charged Lepton Flavor Violation in Muon Channel

    Science.gov (United States)

    Ootani, Wataru

    2016-09-01

    The flavor violating transition between generations of charged leptons is highly suppressed in the Standard Model of the elementary particle physics, whereas many of the promising new physics beyond the Standard Model predict sizable rates of the flavor violating processes within a reach of the ongoing or proposed experiments. The status and the perspectives of the experimental quests for the charged lepton flavor violation in muon channel are reviewed focusing on the three major processes, μ - N to e - N, μ + to e + γ , and μ + to e + e - e + .

  16. Photoinduced intramolecular charge transfer of sodium 4-(N,N-dimethylamino)benzenesulfonate

    Institute of Scientific and Technical Information of China (English)

    林丽榕; 江云宝

    2000-01-01

    A new dual fluorescent N,N-dimethylaniline derivative, sodium 4-(N,N-dimethylamino)-benzenesulfonate (SDMAS), is reported. In SDMAS, the electron acceptor is linked to the phenyl ring via a sulfur atom at the para-position of the electron donor. It was found that SDMAS emits dual fluorescence only in highly polar solvent water but not in organic solvents such as formamide, methanol and acetonitrile. In organic solvents only a single-band emission at ca.360 nm was observed in the short wavelength region. The dual fluorescence of SDMAS in water was found at 365 and 475 nm, respectively. Introduction of organic solvent such as ethanol, acetonitrile, and 1,4-dioxane into aqueous solution of SDMAS leads to blue-shift and quenching of the long-wavelength emission. Measurements of steady-state and picosecond time-resolved fluorescence indicate that the long wavelength fluorescence is emitted from a charge transfer (CT) state that is populated from the locally excited (LE) state, with the latter giving off the

  17. A novel SCN9A mutation responsible for primary erythromelalgia and is resistant to the treatment of sodium channel blockers.

    Directory of Open Access Journals (Sweden)

    Min-Tzu Wu

    Full Text Available Primary erythromelalgia (PE is an autosomal dominant neurological disorder characterized by severe burning pain and erythema in the extremities upon heat stimuli or exercise. Mutations in human SCN9A gene, encoding the α-subunit of the voltage-gated sodium channel, Na(v1.7, were found to be responsible for PE. Three missense mutations of SCN9A gene have recently been identified in Taiwanese patients including a familial (I136V and two sporadic mutations (I848T, V1316A. V1316A is a novel mutation and has not been characterized yet. Topologically, I136V is located in DI/S1 segment and both I848T and V1316A are located in S4-S5 linker region of DII and DIII domains, respectively. To characterize the elelctrophysiological manifestations, the channel conductance with whole-cell patch clamp was recorded on the over-expressed Chinese hamster overy cells. As compared with wild type, the mutant channels showed a significant hyperpolarizing shift in voltage dependent activation and a depolarizing shift in steady-state fast inactivation. The recovery time from channel inactivation is faster in the mutant than in the wild type channels. Since warmth can trigger and exacerbate symptoms, we then examine the influence of tempearture on the sodium channel conduction. At 35°C, I136V and V1316A mutant channels exhibit a further hyperpolarizing shift at activation as compared with wild type channel, even though wild type channel also produced a significant hyperpolarizing shift compared to that of 25°C. High temperature caused a significant depolarizing shift in steady-state fast inactivation in all three mutant channels. These findings may confer to the hyperexcitability of sensory neurons, especially at high temperature. In order to identifying an effective treatment, we tested the IC₅₀ values of selective sodium channel blockers, lidocaine and mexiletine. The IC₅₀ for mexiletine is lower for I848T mutant channel as compared to that of the wild type

  18. Preclinical evaluation of marketed sodium channel blockers in a rat model of myotonia discloses promising antimyotonic drugs.

    Science.gov (United States)

    Desaphy, Jean-François; Carbonara, Roberta; Costanza, Teresa; Conte Camerino, Diana

    2014-05-01

    Although the sodium channel blocker mexiletine is considered the first-line drug in myotonia, some patients experiment adverse effects, while others do not gain any benefit. Other antimyotonic drugs are thus needed to offer mexiletine alternatives. In the present study, we used a previously-validated rat model of myotonia congenita to compare six marketed sodium channel blockers to mexiletine. Myotonia was induced in the rat by injection of anthracen-9-carboxylic acid, a muscle chloride channel blocker. The drugs were given orally and myotonia was evaluated by measuring the time of righting reflex. The drugs were also tested on sodium currents recorded in a cell line transfected with the human skeletal muscle sodium channel hNav1.4 using patch-clamp technique. In vivo, carbamazepine and propafenone showed antimyotonic activity at doses similar to mexiletine (ED50 close to 5mg/kg); flecainide and orphenadrine showed greater potency (ED50 near 1mg/kg); lubeluzole and riluzole were the more potent (ED50 near 0.1mg/kg). The antimyotonic activity of drugs in vivo was linearly correlated with their potency in blocking hNav1.4 channels in vitro. Deviation was observed for propafenone and carbamazepine, likely due to pharmacokinetics and multiple targets. The comparison of the antimyotonic dose calculated in rats with the current clinical dose in humans strongly suggests that all the tested drugs may be used safely for the treatment of human myotonia. Considering the limits of mexiletine tolerability and the occurrence of non-responders, this study proposes an arsenal of alternative drugs, which may prove useful to increase the quality of life of individuals suffering from non-dystrophic myotonia. Further clinical trials are warranted to confirm these results. PMID:24613829

  19. Multiple origins of the sodium channel kdr mutations in codling moth populations.

    Directory of Open Access Journals (Sweden)

    Pierre Franck

    Full Text Available Resistance to insecticides is one interesting example of a rapid current evolutionary change. DNA variability in the voltage-gated sodium channel gene (trans-membrane segments 5 and 6 in domain II was investigated in order to estimate resistance evolution to pyrethroid in codling moth populations at the World level. DNA variation among 38 sequences revealed a unique kdr mutation (L1014F involved in pyrethroid resistance in this gene region, which likely resulted from several convergent substitutions. The analysis of codling moth samples from 52 apple orchards in 19 countries using a simple PCR-RFLP confirmed that this kdr mutation is almost worldwide distributed. The proportions of kdr mutation were negatively correlated with the annual temperatures in the sampled regions. Homozygous kdr genotypes in the French apple orchards showed lower P450 cytochrome oxidase activities than other genotypes. The most plausible interpretation of the geographic distribution of kdr in codling moth populations is that it has both multiple independent origins and a spreading limited by low temperature and negative interaction with the presence of alternative resistance mechanisms to pyrethroid in the populations.

  20. The t-channel Charged Higgs Production in Single Top Events at LHC

    CERN Document Server

    Hashemi, Majid; Bakhshalizadeh, Hossein

    2015-01-01

    In this paper, the t-channel charged Higgs production at LHC is studied. Production process is a t-channel single top event with charged Higgs exchange. Therefore the signal is similar with Standard Model single top production in terms of the final state. In the first step, the signal cross section is calculated and compared to the other main production processes which are used for a heavy charged Higgs search at LHC, i.e., pp -> tbH- and pp -> H+ -> tb. In the next step, an event generation and analysis is applied on signal and background events, in order to estimate the signal significance. The signal cross section is typically smaller than the associated production (tbH-) and resonance production (tb) by a factor of 10-3 and ranges from 10 fb to 1 fb for charged Higgs mass from 200 to 500 GeV at tanbeta = 50. Due to the small cross section of signal events and large SM background, the signal significance is small even after a dedicated kinematic analysis and selection of events, however, tanbeta values abo...

  1. Observability of Charged Higgs Contribution in t-channel Single Top at LHC

    Science.gov (United States)

    Hashemi, Majid; Zebarjad, Seyyed Mohammad; Bakhshalizadeh, Hossein

    2016-05-01

    In this paper, the charged Higgs contribution in t-channel single top production is studied. The production process is a t-channel single top event with charged Higgs exchange. Therefore the signal is similar with Standard Model single top production in terms of the final state. In the first step, the signal cross section is calculated and compared to the other main production processes which are used for a heavy charged Higgs search at LHC, i.e., pp→ tbar {b}H- and pp→ H+ → tbar {b}. In the next step, an event generation and analysis is applied on signal and background events, in order to estimate the signal significance. The signal cross section is typically smaller than the associated production (tbar {b}H-) and resonance production (tbar {b}) by a factor of 10-3 and ranges from 10 f b to 1 f b for charged Higgs mass from 200 to 500 GeV at tan β = 50. Due to the small cross section of signal events and large SM background, the signal significance is small even after a dedicated kinematic analysis and selection of events, however, tan β values above 120 can be excluded at an integrated luminosity of 3000 f b -1.

  2. Impact of Interface Fixed Charges on the Performance of the Channel Material Engineered Cylindrical Nanowire MOSFET

    Directory of Open Access Journals (Sweden)

    Rajni Gautam

    2011-10-01

    Full Text Available The paper presents a simulation study of effect of interface fixed charges on the performance of thecylindrical nanowire MOSFET for different channel materials (Si, GaAs and Ge. The objective of thepresent work is to study the effect of hot carrier damage/stress induced damage/process damage/radiationdamage induced fixed charges at the semiconductor-oxide interface of the cylindrical nanowire MOSFET.Also the circuit reliability issues of the device are discussed in terms of the performance degradation due tointerface fixed charges. The performance has been compared for the three materials in terms of draincurrent driving capability, Ion/Ioff ratio, early voltage, transconductance, parasitic gate capacitance,intrinsic delay, current gain and power gain of the device.

  3. Impact of Interface Fixed Charges on the Performance of the Channel Material Engineered Cylindrical Nanowire MOSFET

    Directory of Open Access Journals (Sweden)

    Rajni Gautam

    2011-09-01

    Full Text Available The paper presents a simulation study of effect of interface fixed charges on the performance of the cylindrical nano wire MOSFET for different channel materials (Si, GaAs and Ge. The objective of the present work is to study the effect of hot carrier damage/stress induced damage/process damage/radiation damage induced fixed charges at the semiconductor-oxide interface of the cylindrical nano wire MOSFET.Also the circuit reliability issues of the device are discussed in terms of the performance degradation due to interface fixed charges. The performance has been compared for the three materials in terms of drain current driving capability, Ion/Ioff ratio, early voltage, trans conductance, parasitic gate capacitance,intrinsic delay, current gain and power gain of the device.

  4. Spider-venom peptides that target voltage-gated sodium channels: pharmacological tools and potential therapeutic leads.

    Science.gov (United States)

    Klint, Julie K; Senff, Sebastian; Rupasinghe, Darshani B; Er, Sing Yan; Herzig, Volker; Nicholson, Graham M; King, Glenn F

    2012-09-15

    Voltage-gated sodium (Na(V)) channels play a central role in the propagation of action potentials in excitable cells in both humans and insects. Many venomous animals have therefore evolved toxins that modulate the activity of Na(V) channels in order to subdue their prey and deter predators. Spider venoms in particular are rich in Na(V) channel modulators, with one-third of all known ion channel toxins from spider venoms acting on Na(V) channels. Here we review the landscape of spider-venom peptides that have so far been described to target vertebrate or invertebrate Na(V) channels. These peptides fall into 12 distinct families based on their primary structure and cysteine scaffold. Some of these peptides have become useful pharmacological tools, while others have potential as therapeutic leads because they target specific Na(V) channel subtypes that are considered to be important analgesic targets. Spider venoms are conservatively predicted to contain more than 10 million bioactive peptides and so far only 0.01% of this diversity been characterised. Thus, it is likely that future research will reveal additional structural classes of spider-venom peptides that target Na(V) channels.

  5. (Almost) Stationary Isotachophoretic Concentration Boundary in a Nanofluidic Channel Using Charge Inversion.

    Science.gov (United States)

    Loessberg-Zahl, Josh; Janssen, Kjeld G H; McCallum, Christopher; Gillespie, Dirk; Pennathur, Sumita

    2016-06-21

    The present work is an experimental study of a new means to induce a quasi-stationary boundary for concentration or separation in a nanochannel induced by charge inversion. Instead of using pressure-driven counter-flow to keep the front stationary, we exploit charge inversion by a highly charged electrolyte, Ru(bpy)3Cl2, that changes the sign of the zeta potential in part of the channel from negative to positive. Having a non-charge inverting electrolyte (MgCl2) in the other part of the channel and applying an electric field can create a standing front at the interface between them without added dispersion due to an externally applied pressure-driven counterflow. The resulting slow moving front position can be easily imaged optically since Ru(bpy)3Cl2 is fluorescent. A simple analytical model for the velocity field and front axial position that reproduces the experimental location of the front shows that the location can be tuned by changing the concentration of the electrolytes (and thus local zeta potential). Both of these give the charge inversion-mediated boundary significant advantages over current methods of concentration and separation and the method is, therefore, of particular importance to chemical and biochemical analysis systems such as chromatography and separations and for enhancing the stacking performance of field amplified sample injection and isotachophoresis. By choosing a non-charge inverting electrolyte other than MgCl2, either this electrolyte or the Ru(bpy)3Cl2 solution can be made to be the leading or trailing electrolyte.

  6. Congruent pattern of accessibility identifies minimal pore gate in a non-symmetric voltage-gated sodium channel.

    Science.gov (United States)

    Oelstrom, Kevin; Chanda, Baron

    2016-01-01

    Opening and closing of the central ion-conducting pore in voltage-dependent ion channels is gated by changes in membrane potential. Although a gate residue in the eukaryotic voltage-gated sodium channel has been identified, the minimal molecular determinants of this gate region remain unknown. Here, by measuring the closed- and open-state reactivity of MTSET to substituted cysteines in all the pore-lining helices, we show that the state-dependent accessibility is delineated by four hydrophobic residues at homologous positions in each domain. Introduced cysteines above these sites do not react with intracellular MTSET while the channels are closed and yet are rapidly modified while the channels are open. These findings, in conjunction with state-dependent metal cross-bridging, support the notion that the gate residues in each of the four S6 segments of the eukaryotic sodium channel form an occlusion for ions in the closed state and are splayed open on activation. PMID:27186888

  7. Alternative splicing modulates inactivation of type 1 voltage-gated sodium channels by toggling an amino acid in the first S3-S4 linker.

    Science.gov (United States)

    Fletcher, Emily V; Kullmann, Dimitri M; Schorge, Stephanie

    2011-10-21

    Voltage-gated sodium channels underlie the upstroke of action potentials and are fundamental to neuronal excitability. Small changes in the behavior of these channels are sufficient to change neuronal firing and trigger seizures. These channels are subject to highly conserved alternative splicing, affecting the short linker between the third transmembrane segment (S3) and the voltage sensor (S4) in their first domain. The biophysical consequences of this alternative splicing are incompletely understood. Here we focus on type 1 sodium channels (Nav1.1) that are implicated in human epilepsy. We show that the functional consequences of alternative splicing are highly sensitive to recording conditions, including the identity of the major intracellular anion and the recording temperature. In particular, the inactivation kinetics of channels containing the alternate exon 5N are more sensitive to intracellular fluoride ions and to changing temperature than channels containing exon 5A. Moreover, Nav1.1 channels containing exon 5N recover from inactivation more rapidly at physiological temperatures. Three amino acids differ between exons 5A and 5N. However, the changes in sensitivity and stability of inactivation were reproduced by a single conserved change from aspartate to asparagine in channels containing exon 5A, which was sufficient to make them behave like channels containing the complete exon 5N sequence. These data suggest that splicing at this site can modify the inactivation of sodium channels and reveal a possible interaction between splicing and anti-epileptic drugs that stabilize sodium channel inactivation.

  8. Charged Higgs boson in the W± Higgs channel at the Large Hadron Collider

    Directory of Open Access Journals (Sweden)

    Rikard Enberg

    2015-04-01

    Full Text Available In light of the recent discovery of a neutral Higgs boson, Hobs, with a mass near 125 GeV, we reassess the LHC discovery potential of a charged Higgs boson, H±, in the W±Hobs decay channel. This decay channel can be particularly important for a H± heavier than the top quark, when it is produced through the pp→tH± process. The knowledge of the mass of Hobs provides an additional handle in the kinematic selection when reconstructing a Breit–Wigner resonance in the Hobs→bb¯ decay channel. We consider some extensions of the Standard Model Higgs sector, with and without supersymmetry, and perform a dedicated signal-to-background analysis to test the scope of this channel for the LHC running at the design energy (14 TeV, for 300 fb−1 (standard and 3000 fb−1 (high integrated luminosities. We find that, while this channel does not show much promise for a supersymmetric H± state, significant portions of the parameter spaces of several two-Higgs doublet models are testable.

  9. Molecular basis of the remarkable species selectivity of an insecticidal sodium channel toxin from the African spider Augacephalus ezendami

    Science.gov (United States)

    Herzig, Volker; Ikonomopoulou, Maria; Smith, Jennifer J.; Dziemborowicz, Sławomir; Gilchrist, John; Kuhn-Nentwig, Lucia; Rezende, Fernanda Oliveira; Moreira, Luciano Andrade; Nicholson, Graham M.; Bosmans, Frank; King, Glenn F.

    2016-01-01

    The inexorable decline in the armament of registered chemical insecticides has stimulated research into environmentally-friendly alternatives. Insecticidal spider-venom peptides are promising candidates for bioinsecticide development but it is challenging to find peptides that are specific for targeted pests. In the present study, we isolated an insecticidal peptide (Ae1a) from venom of the African spider Augacephalus ezendami (family Theraphosidae). Injection of Ae1a into sheep blowflies (Lucilia cuprina) induced rapid but reversible paralysis. In striking contrast, Ae1a was lethal to closely related fruit flies (Drosophila melanogaster) but induced no adverse effects in the recalcitrant lepidopteran pest Helicoverpa armigera. Electrophysiological experiments revealed that Ae1a potently inhibits the voltage-gated sodium channel BgNaV1 from the German cockroach Blattella germanica by shifting the threshold for channel activation to more depolarized potentials. In contrast, Ae1a failed to significantly affect sodium currents in dorsal unpaired median neurons from the American cockroach Periplaneta americana. We show that Ae1a interacts with the domain II voltage sensor and that sensitivity to the toxin is conferred by natural sequence variations in the S1–S2 loop of domain II. The phyletic specificity of Ae1a provides crucial information for development of sodium channel insecticides that target key insect pests without harming beneficial species. PMID:27383378

  10. The $s$-channel Charged Higgs in the Fully Hadronic Final State at LHC

    CERN Document Server

    Ahmed, Ijaz

    2016-01-01

    With the current measurements performed by CMS and ATLAS experiments, the light charged Higgs scenario ($m_{H^{\\pm}}$ $<$ 160 GeV), is excluded for most of the parameter space in the context of MSSM. However, there is still possibility to look for heavy charged Higgs boson particularly in the $s$-channel single top production process where the charged Higgs may appear as a heavy resonance state and decay to $t\\bar{b}$. The production process under consideration in this paper is $pp \\ra H^{\\pm} \\ra t\\bar{b}~+~h.c.$, where the top quark decays to $W^{+}b$ and $W^{+}$ boson subsequently decays to two light jets. It is shown that despite the presence of large QCD and electroweak background events, the charged Higgs signal can be extracted and observed at a large area of MSSM parameter space ($m_{H^{\\pm}}$,tan$\\beta$) at LHC. The observability of charged Higgs is potentially demonstrated with 5$\\sigma$ contours and $95\\%$ confidence level exclusion curves at different integrated LHC luminosities assuming a nomi...

  11. The s-channel charged Higgs in the fully hadronic final state at LHC

    Energy Technology Data Exchange (ETDEWEB)

    Ahmed, Ijaz [University of Malaya, National Center for Particle Physics, Kuala Lumpur (Malaysia); COMSATS Institute of Information Technology (CIIT), Islamabad (Pakistan); Hashemi, Majid [Shiraz University, Physics Department and Biruni Observatory, College of Sciences, Shiraz (Iran, Islamic Republic of); Tajuddin, Wan Ahmad [University of Malaya, National Center for Particle Physics, Kuala Lumpur (Malaysia)

    2016-04-15

    With the current measurements performed by CMS and ATLAS experiments, the light charged Higgs scenario (m{sub H}{sup {sub ±}} < 160 GeV), is excluded for most of the parameter space in the context of MSSM. However, there is still possibility to look for heavy charged Higgs boson particularly in the s-channel single top production process where the charged Higgs may appear as a heavy resonance state and decay to t anti b. The production process under consideration in this paper is pp → H{sup ±} → t anti b + h.c., where the top quark decays to W{sup +}b and W{sup +} boson subsequently decays to two light jets. It is shown that despite the presence of large QCD and electroweak background events, the charged Higgs signal can be extracted and observed at a large area of MSSM parameter space (m{sub H}{sup {sub ±}}, tanβ) at LHC. The observability of charged Higgs is potentially demonstrated with 5σ contours and 95% confidence level exclusion curves at different integrated LHC luminosities assuming a nominal center of mass energy of √(s) = 14 TeV. (orig.)

  12. Ischemia-related subcellular redistribution of sodium channels enhances the proarrhythmic effect of class I antiarrhythmic drugs: a simulation study.

    Directory of Open Access Journals (Sweden)

    Kunichika Tsumoto

    Full Text Available Cardiomyocytes located at the ischemic border zone of infarcted ventricle are accompanied by redistribution of gap junctions, which mediate electrical transmission between cardiomyocytes. This ischemic border zone provides an arrhythmogenic substrate. It was also shown that sodium (Na+ channels are redistributed within myocytes located in the ischemic border zone. However, the roles of the subcellular redistribution of Na+ channels in the arrhythmogenicity under ischemia remain unclear.Computer simulations of excitation conduction were performed in a myofiber model incorporating both subcellular Na+ channel redistribution and the electric field mechanism, taking into account the intercellular cleft potentials.We found in the myofiber model that the subcellular redistribution of the Na+ channels under myocardial ischemia, decreasing in Na+ channel expression of the lateral cell membrane of each myocyte, decreased the tissue excitability, resulting in conduction slowing even without any ischemia-related electrophysiological change. The conventional model (i.e., without the electric field mechanism did not reproduce the conduction slowing caused by the subcellular Na+ channel redistribution. Furthermore, Na+ channel blockade with the coexistence of a non-ischemic zone with an ischemic border zone expanded the vulnerable period for reentrant tachyarrhythmias compared to the model without the ischemic border zone. Na+ channel blockade tended to cause unidirectional conduction block at sites near the ischemic border zone. Thus, such a unidirectional conduction block induced by a premature stimulus at sites near the ischemic border zone is associated with the initiation of reentrant tachyarrhythmias.Proarrhythmia of Na+ channel blockade in patients with old myocardial infarction might be partly attributable to the ischemia-related subcellular Na+ channel redistribution.

  13. A distinct sodium channel voltage-sensor locus determines insect selectivity of the spider toxin Dc1a

    Science.gov (United States)

    Bende, Niraj S.; Dziemborowicz, Sławomir; Mobli, Mehdi; Herzig, Volker; Gilchrist, John; Wagner, Jordan; Nicholson, Graham M.; King, Glenn F.; Bosmans, Frank

    2014-07-01

    β-Diguetoxin-Dc1a (Dc1a) is a toxin from the desert bush spider Diguetia canities that incapacitates insects at concentrations that are non-toxic to mammals. Dc1a promotes opening of German cockroach voltage-gated sodium (Nav) channels (BgNav1), whereas human Nav channels are insensitive. Here, by transplanting commonly targeted S3b-S4 paddle motifs within BgNav1 voltage sensors into Kv2.1, we find that Dc1a interacts with the domain II voltage sensor. In contrast, Dc1a has little effect on sodium currents mediated by PaNav1 channels from the American cockroach even though their domain II paddle motifs are identical. When exploring regions responsible for PaNav1 resistance to Dc1a, we identified two residues within the BgNav1 domain II S1-S2 loop that when mutated to their PaNav1 counterparts drastically reduce toxin susceptibility. Overall, our results reveal a distinct region within insect Nav channels that helps determine Dc1a sensitivity, a concept that will be valuable for the design of insect-selective insecticides.

  14. Conserved charged amino acid residues in the extracellular region of sodium/iodide symporter are critical for iodide transport activity

    Directory of Open Access Journals (Sweden)

    Liang Ji-An

    2010-11-01

    Full Text Available Abstract Background Sodium/iodide symporter (NIS mediates the active transport and accumulation of iodide from the blood into the thyroid gland. His-226 located in the extracellular region of NIS has been demonstrated to be critical for iodide transport in our previous study. The conserved charged amino acid residues in the extracellular region of NIS were therefore characterized in this study. Methods Fourteen charged residues (Arg-9, Glu-79, Arg-82, Lys-86, Asp-163, His-226, Arg-228, Asp-233, Asp-237, Arg-239, Arg-241, Asp-311, Asp-322, and Asp-331 were replaced by alanine. Iodide uptake abilities of mutants were evaluated by steady-state and kinetic analysis. The three-dimensional comparative protein structure of NIS was further modeled using sodium/glucose transporter as the reference protein. Results All the NIS mutants were expressed normally in the cells and targeted correctly to the plasma membrane. However, these mutants, except R9A, displayed severe defects on the iodide uptake. Further kinetic analysis revealed that mutations at conserved positively charged amino acid residues in the extracellular region of NIS led to decrease NIS-mediated iodide uptake activity by reducing the maximal rate of iodide transport, while mutations at conserved negatively charged residues led to decrease iodide transport by increasing dissociation between NIS mutants and iodide. Conclusions This is the first report characterizing thoroughly the functional significance of conserved charged amino acid residues in the extracellular region of NIS. Our data suggested that conserved charged amino acid residues, except Arg-9, in the extracellular region of NIS were critical for iodide transport.

  15. Molecular cloning and analysis of zebrafish voltage-gated sodium channel beta subunit genes: implications for the evolution of electrical signaling in vertebrates

    OpenAIRE

    Zhong Tao P; Watanabe Hiroshi; Chopra Sameer S; Roden Dan M

    2007-01-01

    Abstract Background Action potential generation in excitable cells such as myocytes and neurons critically depends on voltage-gated sodium channels. In mammals, sodium channels exist as macromolecular complexes that include a pore-forming alpha subunit and 1 or more modulatory beta subunits. Although alpha subunit genes have been cloned from diverse metazoans including flies, jellyfish, and humans, beta subunits have not previously been identified in any non-mammalian species. To gain further...

  16. Evolutionary Adaptation of the Amino Acid and Codon Usage of the Mosquito Sodium Channel following Insecticide Selection in the Field Mosquitoes

    OpenAIRE

    Qiang Xu; Lee Zhang; Ting Li; Lan Zhang; Lin He; Ke Dong; Nannan Liu

    2012-01-01

    Target site insensitivity resulting from point mutations within the voltage-gated sodium channel of the insect nervous system is known to be of primary importance in the development of resistance to pyrethroid insecticides. This study shifts current research paradigms by conducting, for the first time, a global analysis of all the naturally occurring mutations, both nonsynonymous and synonymous mutations, as well as mutation combinations in the entire mosquito sodium channel of Culex quinquef...

  17. Quantum entanglement in the voltage dependent sodium channel can reproduce the salient features of neuronal action potential initiation

    CERN Document Server

    Summhammer, Johann

    2007-01-01

    We investigate the effects of a quantum entanglement regime within an ion conducting molecule (ion channel) of the neuronal plasma membrane on the onset dynamics of propagating nerve pulses (action potentials). In particular, we model the onset parameters of the sodium current in the Hodgkin Huxley equation as three similar but independent probabilistic mechanisms which become quantum entangled. The underlying physics is general and can involve entanglement between various degrees of freedom underlaying ion transition states or 'gating states' during conduction, e.g. Na$^+$ ions in different channel locations, or different 'affinity' states of ions with atoms lining the sub-regions of the channel protein ('filter-states'). We find that the 'quantum corrected' Hodgkin Huxley equation incorporating entangled systems states can reproduce action potential pulses with the critical onset dynamics observed recently in neocortical neurons in vivo by Naundorf et al. [Nature {\\bf 440}, 1060 (20 April 2006)]. Interestin...

  18. Measurement of light charged particles in the decay channels of medium-mass excited compound nuclei

    CERN Document Server

    Valdre', S; Casini, G; Pasquali, G; Piantelli, S; Carboni, S; Cinausero, M; Gramegna, F; Marchi, T; Baiocco, G; Bardelli, L; Benzoni, G; Bini, M; Blasi, N; Bracco, A; Brambilla, S; Bruno, M; Camera, F; Corsi, A; Crespi, F; Agostino, M D; Degerlier, M; Kravchuk, V L; Leoni, S; Million, B; Montanari, D; Morelli, L; Nannini, A; Nicolini, R; Poggi, G; Vannini, G; Wieland, O; Bednarczyk, P; Ciemała, M; Dudek, J; Fornal, B; Kmiecik, M; Maj, A; Matejska-Minda, M; Mazurek, K; Meczynski, W; Myalski, S; Styczen, J; Zieblinski, M

    2013-01-01

    The 48Ti on 40Ca reactions have been studied at 300 and 600 MeV focusing on the fusion-evaporation (FE) and fusion-fission (FF) exit channels. Energy spectra and multiplicities of the emitted light charged particles have been compared to Monte Carlo simulations based on the statistical model. Indeed, in this mass region (A about 100) models predict that shape transitions can occur at high spin values and relatively scarce data exist in the literature about coincidence measurements between evaporation residues and light charged particles. Signals of shape transitions can be found in the variations of the lineshape of high energy gamma rays emitted from the de-excitation of GDR states gated on different region of angular momenta. For this purpose it is important to keep under control the FE and FF processes, to regulate the statistical model parameters and to control the onset of possible preequilibrium emissions from 300 to 600 MeV bombarding energy.

  19. A fully integrated, monolithic, cryogenic charge sensitive preamplifier using N-channel JFETs and polysilicon resistors

    International Nuclear Information System (INIS)

    In this paper, an integrated charge preamplifier to be used with small (10--30 mm2) Si(Li) and Ge(Li) X-ray detectors is described. The preamplifier is designed to operate at cryogenic temperatures (∼100 K to 160 K) for the best performance. An N-channel JFET process technology for integrated charge sensitive preamplifiers has been developed. The process integrates multiple pinch-off voltage JFETs fabricated in an n-type epitaxial layer on a low resistivity p-type substrate. The process also incorporates polysilicon resistors integrated on the same die as the JFETs. The optimized polysilicon resistors exhibit 1/f noise nearly as good as metal film resistors at the same current. Results for integrated amplifier are discussed

  20. Mutations in sodium channel {beta}-subunit SCN3B are associated with early-onset lone atrial fibrillation

    DEFF Research Database (Denmark)

    Olesen, Morten Salling; Jespersen, Thomas; Nielsen, Jonas Bille;

    2011-01-01

    AIMS: Atrial fibrillation (AF) is the most frequent arrhythmia. Screening of SCN5A-the gene encoding the a-subunit of the cardiac sodium channel-has indicated that disturbances of the sodium current may play a central role in the mechanism of lone AF. We tested the hypothesis that lone AF in young...... patients is associated with genetic mutations in SCN3B and SCN4B, the genes encoding the two ß-subunits of the cardiac sodium channel. METHODS AND RESULTS: In 192 unrelated lone AF patients, the entire coding sequence and splice junctions of SCN3B and SCN4B were bidirectionally sequenced. Three non......-synonymous mutations were found in SCN3B (R6K, L10P, and M161T). Two mutations were novel (R6K and M161T). None of the mutations were present in the control group (n = 432 alleles), nor have any been previously reported in conjunction with AF. All SCN3B mutations affected residues that are evolutionarily conserved...

  1. State-dependent block of rat Nav1.4 sodium channels expressed in xenopus oocytes by pyrazoline-type insecticides.

    Science.gov (United States)

    Silver, Kristopher; Soderlund, David M

    2005-06-01

    Insecticidal pyrazolines inhibit voltage-sensitive sodium channels of both insect and mammalian neurons in a voltage-dependent manner. Studies on the effects of pyrazoline insecticides on mammalian sodium channels have been limited to experimentation on the tetrodotoxin-sensitive (TTX-S) and tetrodotoxin-resistant (TTX-R) sodium channel populations of rat dorsal root ganglion (DRG) neurons. In this study, we examined the effects of the insecticidal pyrazolines indoxacarb, the N-decarbomethoxyllated metabolite of indoxacarb (DCJW), and RH 3421 on rat Na(v)1.4 sodium channels expressed in Xenopus laevis oocytes using the two-electrode voltage clamp technique. Both DCJW and RH 3421 were ineffective inhibitors of rat Na(v)1.4 sodium channels at a membrane potential of -120 mV, but depolarization to -60 mV or -30 mV during insecticide exposure resulted in substantial block. Inhibition by pyrazoline insecticides was nearly irreversible with washout, but repolarization of the membrane relieved block. DCJW and RH 3421 also caused hyperpolarizing shifts in the voltage dependence of slow inactivation without affecting the voltage dependence of activation or fast inactivation. These results suggest that DCJW and RH 3421 interact specifically with the slow inactivated state of the sodium channel. Indoxacarb did not cause block at any potential, yet it interfered with the ability of DCJW, but not RH 3421, to inhibit sodium current. Phenytoin, an anticonvulsant, reduced the efficacy of both DCJW and RH 3421. These data imply that the binding site for pyrazoline insecticides overlaps with that for therapeutic sodium channel blockers.

  2. RNAi-mediated knockdown of the voltage gated sodium ion channel TcNav causes mortality in Tribolium castaneum

    Science.gov (United States)

    Abd El Halim, Hesham M.; Alshukri, Baida M. H.; Ahmad, Munawar S.; Nakasu, Erich Y. T.; Awwad, Mohammed H.; Salama, Elham M.; Gatehouse, Angharad M. R.; Edwards, Martin G.

    2016-01-01

    The voltage-gated sodium ion channel (VGSC) belongs to the largest superfamily of ion channels. Since VGSCs play key roles in physiological processes they are major targets for effective insecticides. RNA interference (RNAi) is widely used to analyse gene function, but recently, it has shown potential to contribute to novel strategies for selectively controlling agricultural insect pests. The current study evaluates the delivery of dsRNA targeted to the sodium ion channel paralytic A (TcNav) gene in Tribolium castaneum as a viable means of controlling this insect pest. Delivery of TcNav dsRNA caused severe developmental arrest with larval mortalities up to 73% post injection of dsRNA. Injected larvae showed significant (p < 0.05) knockdown in gene expression between 30–60%. Expression was also significantly (p < 0.05) reduced in pupae following injection causing 30% and 42% knockdown for early and late pupal stages, respectively. Oral delivery of dsRNA caused dose-dependant mortalities of between 19 and 51.34%; this was accompanied by significant (p < 0.05) knockdown in gene expression following 3 days of continuous feeding. The majority of larvae injected with, or fed, dsRNA died during the final larval stage prior to pupation. This work provides evidence of a viable RNAi-based strategy for insect control. PMID:27411529

  3. Pertussis toxin modulation of sodium channels in the central neurons of cyhalothrin-resistant and cyhalothrin-susceptible cotton bollworm, Helicoverpa armigera

    Institute of Scientific and Technical Information of China (English)

    QIANG ZHAO; DE-LING KONG; BING-JUN HE; YAN-QIANG LIU; XIAN-LIN FAN; AN-XI LIU

    2007-01-01

    Pertussis toxin (PTX) inhibits the activation of the α-subunit of the inhibitory heterotrimeric G-proteins (Gαi/o) and modulates voltage-gated sodium channels, which may be one of the primary targets of pyrethroids. To investigate the potential mechanisms of agricultural pests resistance to pyrethroid insecticides, we examined the modulations by PTX on sodium channels in the central neurons of the 3rd-4th instar larvae of cyhalothrin-resistant (Cy-R) and cyhalothrin-susceptible (Cy-S) Helicoverpa armigera by the whole-cell patch-clamp technique.The isolated neurons were cultured for 12-16 h in an improved L15 insect culture medium with or without PTX (400 ng/mL). The results showed that both the Cy-R and Cy-S sodium channels exhibited fast kinetics and tetrodotoxin (TTX) sensitivity. The Cy-R sodium channels exhibited not only altered gating properties, including a 8.88-mV right shift in voltage-dependent activation (V0.5act) and a 6.54-mV right shift in voltage-dependent inactivation (V0.5inact), but also a reduced peak in sodium channel density (Idensity) (55.2% of that in Cy-S neurons). Cy-R sodium channels also showed low excitability, as evidenced by right shift of activation potential (Vacti) by 5-10 mV and peak potential (Vpeak) by 20 mV. PTX exerted significant effects on Cy-S sodium channels,reducing sodium channel density by 70.04%, right shifting V0.5act by 14.41 mV and V0.5inact by 9.38 mV. It did not cause any significant changes of the parameters mentioned above in the Cy-R sodium channels. The activation time (Tpeak) from latency to peak at peak voltage and the fast inactivation time constant (τinact) in both Cy-S and Cy-R neurons were not affected. The results suggest that cotton bollworm resistant to pyrethroid insecticides involves not only mutations and allosteric alterations of voltage-gated sodium channels, but also might implicate perturbation of PTX-sensitive Gαi/o-coupled signaling transduction pathways.

  4. [Effect of Segestria florentina spider venom on the mechanism of inactivation of sodium channels].

    Science.gov (United States)

    Usmanov, P B; Kalikulov, D; Nasledov, G A; Tashmukhamedov, B A

    1985-01-01

    It was shown that Segestria florentina spider venom mainly reduces the rate and amount of sodium inactivation. This effect is likely to be responsible for the prolongation of the action potential. PMID:2413900

  5. Cardiac sodium channel Na(v)1.5 interacts with and is regulated by the protein tyrosine phosphatase PTPH1

    DEFF Research Database (Denmark)

    Jespersen, Thomas; Gavillet, Bruno; van Bemmelen, Miguel X;

    2006-01-01

    In order to identify proteins interacting with the cardiac voltage-gated sodium channel Na(v)1.5, we used the last 66 amino acids of the C-terminus of the channel as bait to screen a human cardiac cDNA library. We identified the protein tyrosine phosphatase PTPH1 as an interacting protein. Pull...

  6. Space charge effect measurements for a multi-channel ionization chamber used for synchrotron radiation

    Energy Technology Data Exchange (ETDEWEB)

    Nasr, Amgad

    2012-07-18

    In vivo coronary angiography is one of the techniques used to investigate the heart diseases, by using catheter to inject a contrast medium of a given absorption coefficient into the heart vessels. Taking X-ray images produced by X-ray tube or synchrotron radiation for visualizing the blood in the coronary arteries. As the synchrotron radiation generated by the relativistic charged particle at the bending magnets, which emits high intensity photons in comparison with the X-ray tube. The intensity of the synchrotron radiation is varies with time. However for medical imaging it's necessary to measure the incoming intensity with the integrated time. The thesis work includes building a Multi-channel ionization chamber which can be filled with noble gases N{sub 2}, Ar and Xe with controlled inner pressure up to 30 bar. This affects the better absorption efficiency in measuring the high intensity synchrotron beam fluctuation. The detector is a part of the experimental setup used in the k-edge digital subtraction angiography project, which will be used for correcting the angiography images taken by another detector at the same time. The Multi-channel ionization chamber calibration characteristics are measured using 2 kW X-ray tube with molybdenum anode with characteristic energy of 17.44 keV. According to the fast drift velocity of the electrons relative to the positive ions, the electrons will be collected faster at the anode and will induce current signals, while the positive ions is still drifting towards the cathode. However the accumulation of the slow ions inside the detector disturbs the homogeneous applied electric field and leads to what is known a space charge effect. In this work the space charge effect is measured with very high synchrotron photons intensity from EDR beam line at BESSYII. The strong attenuation in the measured amplitude signal occurs when operating the chamber in the recombination region. A plateau is observed at the amplitude signal when

  7. The effects of huwentoxin-I on the voltage-gated sodium channels of rat hippocampal and cockroach dorsal unpaired median neurons.

    Science.gov (United States)

    Wang, Meichi; Rong, Mingqiang; Xiao, Yucheng; Liang, Songping

    2012-03-01

    Huwentoxin-I (HWTX-I) is a 33-residue peptide isolated from the venom of Ornithoctonus huwena and could inhibit TTX-sensitive voltage-gated sodium channels and N-type calcium channels in mammalian dorsal root ganglion (DRG) neurons. However, the effects of HWTX-I on mammalian central neuronal and insect sodium channel subtypes remain unknown. In this study, we found that HWTX-I potently inhibited sodium channels in rat hippocampal and cockroach dorsal unpaired median (DUM) neurons with the IC(50) values of 66.1±5.2 and 4.80±0.58nM, respectively. Taken together with our previous work on DRG neurons (IC(50)≈55nM), the order of sodium channel sensitivity to HWTX-I inhibition was insect central DUM≫mammalian peripheral>mammalian central neurons. HWTX-I exhibited no effect on the steady-state activation and inactivation of sodium channels in rat hippocampal and cockroach DUM neurons. PMID:22094230

  8. Cloning of Partial Sodium Channel Gene From Strains of Fenvalerate-Resistant and Susceptible Cotton Aphid(Aphis gossypii Glover)

    Institute of Scientific and Technical Information of China (English)

    SUN Lu-juan; GAO Xi-wu; ZHENG Bing-zong

    2003-01-01

    The strain of fenvalerate-resistant cotton aphids was selected using fenvalerate insecticide in the laboratory, the resistance factor of the strain was 199.54. Three degenerate primers were designed and used to perform PCR amplification. A cDNA encoding partial sodium channel gene was cloned from the fenvalerate-resistant and -susceptible strains. There were two nucleotide acid differences between fenvalerate-resistant strain and -susceptible strain, resulting in an amino acid mutation, Met→Leu. It is predicted that the mutation is related to the cotton aphid resistance to fenvalerate.

  9. Atrial-selective prolongation of refractory period with AVE0118 is due principally to inhibition of sodium channel activity

    OpenAIRE

    Burashnikov, Alexander; Barajas-Martinez, Hector; Hu, Dan; Nof, Eyal; Blazek, Jonathan; Antzelevitch, Charles

    2012-01-01

    AVE0118’s action to prolong effective refractory period (ERP) in atria but not ventricles is thought to be due to its inhibition of IKur. However, in non-remodeled atria, AVE0118 prolongs ERP but not action potential duration (APD70-90), which can be explained with inhibition of sodium, but not potassium channel current. ERP, APD, and the maximum rate of rise of the AP upstroke (Vmax) were measured in canine isolated coronary-perfused right atrial and in superfused ventricular tissue preparat...

  10. Activation of the Endogenous Renin-Angiotensin-Aldosterone System or Aldosterone Administration Increases Urinary Exosomal Sodium Channel Excretion.

    Science.gov (United States)

    Qi, Ying; Wang, Xiaojing; Rose, Kristie L; MacDonald, W Hayes; Zhang, Bing; Schey, Kevin L; Luther, James M

    2016-02-01

    Urinary exosomes secreted by multiple cell types in the kidney may participate in intercellular signaling and provide an enriched source of kidney-specific proteins for biomarker discovery. Factors that alter the exosomal protein content remain unknown. To determine whether endogenous and exogenous hormones modify urinary exosomal protein content, we analyzed samples from 14 mildly hypertensive patients in a crossover study during a high-sodium (HS, 160 mmol/d) diet and low-sodium (LS, 20 mmol/d) diet to activate the endogenous renin-angiotensin-aldosterone system. We further analyzed selected exosomal protein content in a separate cohort of healthy persons receiving intravenous aldosterone (0.7 μg/kg per hour for 10 hours) versus vehicle infusion. The LS diet increased plasma renin activity and aldosterone concentration, whereas aldosterone infusion increased only aldosterone concentration. Protein analysis of paired urine exosome samples by liquid chromatography-tandem mass spectrometry-based multidimensional protein identification technology detected 2775 unique proteins, of which 316 exhibited significantly altered abundance during LS diet. Sodium chloride cotransporter (NCC) and α- and γ-epithelial sodium channel (ENaC) subunits from the discovery set were verified using targeted multiple reaction monitoring mass spectrometry quantified with isotope-labeled peptide standards. Dietary sodium restriction or acute aldosterone infusion similarly increased urine exosomal γENaC[112-122] peptide concentrations nearly 20-fold, which correlated with plasma aldosterone concentration and urinary Na/K ratio. Urine exosomal NCC and αENaC concentrations were relatively unchanged during these interventions. We conclude that urinary exosome content is altered by renin-angiotensin-aldosterone system activation. Urinary measurement of exosomal γENaC[112-122] concentration may provide a useful biomarker of ENaC activation in future clinical studies.

  11. Sodium channel SCN8A (Nav1.6: properties and de novo mutations in epileptic encephalopathy and intellectual disability

    Directory of Open Access Journals (Sweden)

    Janelle Elizabeth O'Brien

    2013-10-01

    Full Text Available The sodium channel Nav1.6, encoded by the gene SCN8A, is one of the major voltage-gated channels in human brain. The sequences of sodium channels have been highly conserved during evolution, and minor changes in biophysical properties can have a major impact in vivo. Insight into the role of Nav1.6 has come from analysis of spontaneous and induced mutations of mouse Scn8a during the past 18 years. Only within the past year has the role of SCN8A in human disease become apparent from whole exome and genome sequences of patients with sporadic disease. Unique features of Nav1.6 include its contribution to persistent current, resurgent current, repetitive neuronal firing, and subcellular localization at the axon initial segment and nodes of Ranvier. Loss of Nav1.6 activity results in reduced neuronal excitability, while gain-of-function mutations can increase neuronal excitability. Mouse Scn8a (med mutants exhibit movement disorders including ataxia, tremor and dystonia. Thus far, more than ten human de novo mutations have been identified in patients with two types of disorders, epileptic encephalopathy and intellectual disability. We review these human mutations as well as the unique features of Nav1.6 that contribute to its role in determining neuronal excitability in vivo. A supplemental figure illustrating the positions of amino acid residues within the 4 domains and 24 transmembrane segments of Nav1.6 is provided to facilitate the location of novel mutations within the channel protein.

  12. Synthesis, crystal structure and charge distribution of Na7As11O31: An oxygen-deficient layered sodium arsenate

    International Nuclear Information System (INIS)

    A new sodium arsenate with layer structure has been synthesized and its crystal structure solved and refined by single-crystal X-ray diffraction. The crystal is trigonal, space group P3-bar m1, a=11.199(3)A, c=5.411(2)A, V=587.80(3)A3, Z=1; the refinement converged to R=0.0282 and wR=0.0751 for 590 reflections with (I)>2sigma(I). The structural model gives the formula Na7As11O32, which would be non-neutral; besides, the structural model is not validated by the charge distribution (CD) analysis, which gives an unsatisfactory agreement on the computed charges of the cations. The CD analysis suggest incomplete (5/6) occupation of the O5 site, which leads to the deficiency of an oxygen atom per unit cell and to formula Na7As11O31: this new structural model corresponds to a neutral compound, is validated by the CD analysis, and results in better displacement parameters for O5 than its non neutral counterpart. The (001) anionic layers are built up from corner and edge sharing of As1 and As2 distorted octahedra and As3 distorted tetrahedra, the sodium cations playing the role of interlayer cations. The effects of the oxygen deficiency on the crystal structure are discussed

  13. Systematic Study of Binding of μ-Conotoxins to the Sodium Channel NaV1.4

    Directory of Open Access Journals (Sweden)

    Somayeh Mahdavi

    2014-12-01

    Full Text Available Voltage-gated sodium channels (NaV are fundamental components of the nervous system. Their dysfunction is implicated in a number of neurological disorders, such as chronic pain, making them potential targets for the treatment of such disorders. The prominence of the NaV channels in the nervous system has been exploited by venomous animals for preying purposes, which have developed toxins that can block the NaV channels, thereby disabling their function. Because of their potency, such toxins could provide drug leads for the treatment of neurological disorders associated with NaV channels. However, most toxins lack selectivity for a given target NaV channel, and improving their selectivity profile among the NaV1 isoforms is essential for their development as drug leads. Computational methods will be very useful in the solution of such design problems, provided accurate models of the protein-ligand complex can be constructed. Using docking and molecular dynamics simulations, we have recently constructed a model for the NaV1.4-μ-conotoxin-GIIIA complex and validated it with the ample mutational data available for this complex. Here, we use the validated NaV1.4 model in a systematic study of binding other μ-conotoxins (PIIIA, KIIIA and BuIIIB to NaV1.4. The binding mode obtained for each complex is shown to be consistent with the available mutation data and binding constants. We compare the binding modes of PIIIA, KIIIA and BuIIIB to that of GIIIA and point out the similarities and differences among them. The detailed information about NaV1.4-μ-conotoxin interactions provided here will be useful in the design of new NaV channel blocking peptides.

  14. Molecular cloning and analysis of zebrafish voltage-gated sodium channel beta subunit genes: implications for the evolution of electrical signaling in vertebrates

    Directory of Open Access Journals (Sweden)

    Zhong Tao P

    2007-07-01

    Full Text Available Abstract Background Action potential generation in excitable cells such as myocytes and neurons critically depends on voltage-gated sodium channels. In mammals, sodium channels exist as macromolecular complexes that include a pore-forming alpha subunit and 1 or more modulatory beta subunits. Although alpha subunit genes have been cloned from diverse metazoans including flies, jellyfish, and humans, beta subunits have not previously been identified in any non-mammalian species. To gain further insight into the evolution of electrical signaling in vertebrates, we investigated beta subunit genes in the teleost Danio rerio (zebrafish. Results We identified and cloned single zebrafish gene homologs for beta1-beta3 (zbeta1-zbeta3 and duplicate genes for beta4 (zbeta4.1, zbeta4.2. Sodium channel beta subunit loci are similarly organized in fish and mammalian genomes. Unlike their mammalian counterparts, zbeta1 and zbeta2 subunit genes display extensive alternative splicing. Zebrafish beta subunit genes and their splice variants are differentially-expressed in excitable tissues, indicating tissue-specific regulation of zbeta1-4 expression and splicing. Co-expression of the genes encoding zbeta1 and the zebrafish sodium channel alpha subunit Nav1.5 in Chinese Hamster Ovary cells increased sodium current and altered channel gating, demonstrating functional interactions between zebrafish alpha and beta subunits. Analysis of the synteny and phylogeny of mammalian, teleost, amphibian, and avian beta subunit and related genes indicated that all extant vertebrate beta subunits are orthologous, that beta2/beta4 and beta1/beta3 share common ancestry, and that beta subunits are closely related to other proteins sharing the V-type immunoglobulin domain structure. Vertebrate sodium channel beta subunit genes were not identified in the genomes of invertebrate chordates and are unrelated to known subunits of the para sodium channel in Drosophila. Conclusion The

  15. Mechanism of action of two insect toxins huwentoxin-III and hainantoxin-VI on voltage-gated sodium channels.

    Science.gov (United States)

    Wang, Rui-lan; Yi, Su; Liang, Song-ping

    2010-06-01

    Selenocosmia huwena and Selenocosmia hainana are two tarantula species found in southern China. Their venoms contain abundant peptide toxins. Two new neurotoxic peptides, huwentoxin-III (HWTX-III) and hainantoxin-VI (HNTX-VI), were obtained from the venom using ion-exchange chromatography and reverse-phase high performance liquid chromatography (RP-HPLC). The mechanism of action of HWTX-III and HNTX-VI on insect neuronal voltage-gated sodium channels (VGSCs) was studied via whole-cell patch clamp techniques. In a fashion similar to delta-atracotoxins, HNTX-VI can induce a slowdown of current inactivation of the VGSC and reduction in the peak of Na+ current in cockroach dorsal unpaired median (DUM) neurons. Meanwhile, 10 micromol/L HNTX-IV caused a positive shift of steady-state inactivation of sodium channel. HWTX-III inhibited VGSCs on DUM neurons (concentration of toxin at half-maximal inhibition (IC(50)) approximately 1.106 micromol/L) in a way much similar to tetrodotoxin (TTX). HWTX-III had no effect on the kinetics of activation and inactivation. The shift in the steady-state inactivation curve was distinct from other depressant spider toxins. The diverse effect and the mechanism of action of the two insect toxins illustrate the diverse biological activities of spider toxins and provide a fresh theoretical foundation to design and develop novel insecticides. PMID:20506577

  16. Mass and charge transport in micro and nano-fluidic channels

    CERN Document Server

    Mortensen, N A; Okkels, F; Bruus, H

    2006-01-01

    We consider laminar flow of incompressible electrolytes in long, straight channels driven by pressure and electro-osmosis. We use a Hilbert space eigenfunction expansion to address the general problem of an arbitrary cross section and obtain general results in linear-response theory for the mass and charge transport coefficients which satisfy Onsager relations. In the limit of non-overlapping Debye layers the transport coefficients are simply expressed in terms of parameters of the electrolyte as well as the hydraulic radius R=2A/P with A and P being the cross-sectional area and perimeter, respectively. In articular, we consider the limits of thin non-overlapping as well as strongly overlapping Debye layers, respectively, and calculate the corrections to the hydraulic resistance due to electro-hydrodynamic interactions.

  17. Suppression of Space Charge Induced Beam Halo in Nonlinear Focusing Channel

    CERN Document Server

    Batygin, Yuri K; Kurennoy, Sergey; Li, Chao

    2016-01-01

    An intense non-uniform particle beam exhibits strong emittance growth and halo formation in focusing channels due to nonlinear space charge forces of the beam. This phenomenon limits beam brightness and results in particle losses. The problem is connected with irreversible distortion of phase space volume of the beam in conventional focusing structures due to filamentation in phase space. Emittance growth is accompanied by halo formation in real space, which results in inevitable particle losses. A new approach for solving a self-consistent problem for a matched non-uniform beam in two-dimensional geometry is discussed. The resulting solution is applied to the problem of beam transport, while avoiding emittance growth and halo formation by the use of nonlinear focusing field. Conservation of a beam distribution function is demonstrated analytically and by particle-in-cell simulation for a beam with a realistic beam distribution.

  18. Suppression of space charge induced beam halo in nonlinear focusing channel

    Science.gov (United States)

    Batygin, Yuri K.; Scheinker, Alexander; Kurennoy, Sergey; Li, Chao

    2016-04-01

    An intense non-uniform particle beam exhibits strong emittance growth and halo formation in focusing channels due to nonlinear space charge forces of the beam. This phenomenon limits beam brightness and results in particle losses. The problem is connected with irreversible distortion of phase space volume of the beam in conventional focusing structures due to filamentation in phase space. Emittance growth is accompanied by halo formation in real space, which results in inevitable particle losses. A new approach for solving a self-consistent problem for a matched non-uniform beam in two-dimensional geometry is discussed. The resulting solution is applied to the problem of beam transport, while avoiding emittance growth and halo formation by the use of nonlinear focusing field. Conservation of a beam distribution function is demonstrated analytically and by particle-in-cell simulation for a beam with a realistic beam distribution.

  19. Nonnuclear Nearly Free Electron Conduction Channels Induced by Doping Charge in Nanotube–Molecular Sheet Composites

    Energy Technology Data Exchange (ETDEWEB)

    Zhao, Jin; Zheng, Qijing; Petek, Hrvoje; Yang, Jinlong

    2014-09-04

    Nearly free electron (NFE) states with density maxima in nonnuclear (NN) voids may have remarkable electron transport properties ranging from suppressed electron–phonon interaction to Wigner crystallization. Such NFE states, however, usually exist near the vacuum level, which makes them unsuitable for transport. Through first principles calculations on nanocomposites consisting of carbon nanotube (CNT) arrays sandwiched between boron nitride (BN) sheets, we describe a stratagem for stabilizing the NN-NFE states to below the Fermi level. By doping the CNTs with negative charge, we establish Coulomb barriers at CNTs walls that, together with the insulating BN sheets, define the transverse potentials of one-dimensional (1D) transport channels, which support the NN-NFE states.

  20. Nonnuclear nearly free electron conduction channels induced by doping charge in nanotube-molecular sheet composites.

    Science.gov (United States)

    Zhao, Jin; Zheng, Qijing; Petek, Hrvoje; Yang, Jinlong

    2014-09-01

    Nearly free electron (NFE) states with density maxima in nonnuclear (NN) voids may have remarkable electron transport properties ranging from suppressed electron-phonon interaction to Wigner crystallization. Such NFE states, however, usually exist near the vacuum level, which makes them unsuitable for transport. Through first principles calculations on nanocomposites consisting of carbon nanotube (CNT) arrays sandwiched between boron nitride (BN) sheets, we describe a stratagem for stabilizing the NN-NFE states to below the Fermi level. By doping the CNTs with negative charge, we establish Coulomb barriers at CNTs walls that, together with the insulating BN sheets, define the transverse potentials of one-dimensional (1D) transport channels, which support the NN-NFE states. PMID:24401149

  1. A design of new multi-channel high precision charge-to-convert (QAC) circuit

    International Nuclear Information System (INIS)

    A new way and circuit designed for multi-channel high precision charge to amplitude conversion (QAC) is introduced in this paper. The new QAC circuit performs the conversion of fast current pulses generated by a photomultiplier tube (PMT) to voltage signals. The output voltage of the QAC circuit is directly fed to the multifunction DAQ. This system is optimal for fast current signals. The new circuit has features such as high precision, high speed of conversion, less components, wide range of input (0-600 pC) and low cost. The circuit that we developed can be widely used to construct front-end read-out electronics of data acquisition system in measurement system of nuclear physics experiment with large-scale detector array. And this design is useful for researching of the ASIC principle model of the circuit in the next step. (authors)

  2. Fast and slow activation kinetics of voltage-gated sodium channels in molluscan neurons.

    Science.gov (United States)

    Gilly, W F; Gillette, R; McFarlane, M

    1997-05-01

    Whole cell patch-clamp recordings of Na current (I(Na)) were made under identical experimental conditions from isolated neurons from cephalopod (Loligo, Octopus) and gastropod (Aplysia, Pleurobranchaea, Doriopsilla) species to compare properties of activation gating. Voltage dependence of peak Na conductance (gNa) is very similar in all cases, but activation kinetics in the gastropod neurons studied are markedly slower. Kinetic differences are very pronounced only over the voltage range spanned by the gNa-voltage relation. At positive and negative extremes of voltage, activation and deactivation kinetics of I(Na) are practically indistinguishable in all species studied. Voltage-dependent rate constants underlying activation of the slow type of Na channel found in gastropods thus appear to be much more voltage dependent than are the equivalent rates in the universally fast type of channel that predominates in cephalopods. Voltage dependence of inactivation kinetics shows a similar pattern and is representative of activation kinetics for the two types of Na channels. Neurons with fast Na channels can thus make much more rapid adjustments in the number of open Na channels at physiologically relevant voltages than would be possible with only slow Na channels. This capability appears to be an adaptation that is highly evolved in cephalopods, which are well known for their high-speed swimming behaviors. Similarities in slow and fast Na channel subtypes in molluscan and mammalian neurons are discussed. PMID:9163364

  3. CK2 activity is required for the interaction of FGF14 with voltage-gated sodium channels and neuronal excitability.

    Science.gov (United States)

    Hsu, Wei-Chun J; Scala, Federico; Nenov, Miroslav N; Wildburger, Norelle C; Elferink, Hannah; Singh, Aditya K; Chesson, Charles B; Buzhdygan, Tetyana; Sohail, Maveen; Shavkunov, Alexander S; Panova, Neli I; Nilsson, Carol L; Rudra, Jai S; Lichti, Cheryl F; Laezza, Fernanda

    2016-06-01

    Recent data shows that fibroblast growth factor 14 (FGF14) binds to and controls the function of the voltage-gated sodium (Nav) channel with phenotypic outcomes on neuronal excitability. Mutations in the FGF14 gene in humans have been associated with brain disorders that are partially recapitulated in Fgf14(-/-) mice. Thus, signaling pathways that modulate the FGF14:Nav channel interaction may be important therapeutic targets. Bioluminescence-based screening of small molecule modulators of the FGF14:Nav1.6 complex identified 4,5,6,7 -: tetrabromobenzotriazole (TBB), a potent casein kinase 2 (CK2) inhibitor, as a strong suppressor of FGF14:Nav1.6 interaction. Inhibition of CK2 through TBB reduces the interaction of FGF14 with Nav1.6 and Nav1.2 channels. Mass spectrometry confirmed direct phosphorylation of FGF14 by CK2 at S228 and S230, and mutation to alanine at these sites modified FGF14 modulation of Nav1.6-mediated currents. In 1 d in vitro hippocampal neurons, TBB induced a reduction in FGF14 expression, a decrease in transient Na(+) current amplitude, and a hyperpolarizing shift in the voltage dependence of Nav channel steady-state inactivation. In mature neurons, TBB reduces the axodendritic polarity of FGF14. In cornu ammonis area 1 hippocampal slices from wild-type mice, TBB impairs neuronal excitability by increasing action potential threshold and lowering firing frequency. Importantly, these changes in excitability are recapitulated in Fgf14(-/-) mice, and deletion of Fgf14 occludes TBB-dependent phenotypes observed in wild-type mice. These results suggest that a CK2-FGF14 axis may regulate Nav channels and neuronal excitability.-Hsu, W.-C. J., Scala, F., Nenov, M. N., Wildburger, N. C., Elferink, H., Singh, A. K., Chesson, C. B., Buzhdygan, T., Sohail, M., Shavkunov, A. S., Panova, N. I., Nilsson, C. L., Rudra, J. S., Lichti, C. F., Laezza, F. CK2 activity is required for the interaction of FGF14 with voltage-gated sodium channels and neuronal

  4. In Liddle Syndrome, Epithelial Sodium Channel Is Hyperactive Mainly in the Early Part of the Aldosterone-Sensitive Distal Nephron.

    Science.gov (United States)

    Nesterov, Viatcheslav; Krueger, Bettina; Bertog, Marko; Dahlmann, Anke; Palmisano, Ralf; Korbmacher, Christoph

    2016-06-01

    The epithelial sodium channel (ENaC) is rate limiting for Na(+) absorption in the aldosterone-sensitive distal nephron comprising the late distal convoluted tubule (DCT2), the connecting tubule (CNT), and the entire collecting duct. Liddle syndrome (pseudohyperaldosteronism), a severe form of salt-sensitive hypertension, is caused by gain-of-function mutations of ENaC, but the precise tubular site of increased ENaC function is unknown. In the cortical collecting duct (CCD), ENaC is known to be regulated by aldosterone. In contrast, we recently reported aldosterone-independent ENaC regulation in the early part of the aldosterone-sensitive distal nephron. Here, we investigated ENaC function in the transition zone of DCT2/CNT or CNT/CCD microdissected from mice homozygous for Liddle syndrome mutation or from wild-type control mice. Whole-cell patch-clamp recordings were used to measure amiloride-sensitive ENaC currents in nephron fragments from mice maintained on different sodium diets to vary plasma aldosterone levels. Our data indicate that in mice with Liddle syndrome, the primary site of increased Na(+) reabsorption is the DCT2/CNT. In addition, increased aldosterone responsiveness of ENaC in CNT/CCD may contribute to salt-sensitive hypertension in Liddle syndrome. Single channel properties of ENaC were similar in Liddle syndrome mutation and wild-type mice, but ENaC expression at the apical membrane was increased in Liddle syndrome mutation when compared with wild-type mice, in particular, in animals maintained on a high salt diet. Our findings highlight the importance of ENaC function and regulation in the early part of the aldosterone-sensitive distal nephron for the maintenance of sodium balance and blood pressure control.

  5. The β1-subunit of Na(v1.5 cardiac sodium channel is required for a dominant negative effect through α-α interaction.

    Directory of Open Access Journals (Sweden)

    Aurélie Mercier

    Full Text Available Brugada syndrome (BrS is an inherited autosomal dominant cardiac channelopathy. Several mutations on the cardiac sodium channel Na(v1.5 which are responsible for BrS lead to misfolded proteins that do not traffic properly to the plasma membrane. In order to mimic patient heterozygosity, a trafficking defective mutant, R1432G was co-expressed with Wild Type (WT Na(v1.5 channels in HEK293T cells. This mutant significantly decreased the membrane Na current density when it was co-transfected with the WT channel. This dominant negative effect did not result in altered biophysical properties of Na(v1.5 channels. Luminometric experiments revealed that the expression of mutant proteins induced a significant reduction in membrane expression of WT channels. Interestingly, we have found that the auxiliary Na channel β(1-subunit was essential for this dominant negative effect. Indeed, the absence of the β(1-subunit prevented the decrease in WT sodium current density and surface proteins associated with the dominant negative effect. Co-immunoprecipitation experiments demonstrated a physical interaction between Na channel α-subunits. This interaction occurred only when the β(1-subunit was present. Our findings reveal a new role for β(1-subunits in cardiac voltage-gated sodium channels by promoting α-α subunit interaction which can lead to a dominant negative effect when one of the α-subunits shows a trafficking defective mutation.

  6. Off-diagonal Yukawa couplings in the s-channel charged Higgs production at LHC

    Directory of Open Access Journals (Sweden)

    Majid Hashemi

    2015-02-01

    Full Text Available The search for the heavy charged Higgs (mH±>mtop has been mainly based on the off-shell top pair production process. However, resonance production in s-channel single top events is an important channel to search for this particle. In a previous work, it was shown that this process, i.e., qq′→H+→tb¯+h.c., can lead to comparable results to what is already obtained from LHC searches. What was obtained was, however, based on diagonal Yukawa couplings between incoming quarks assuming cs¯ as the main incoming pair due to the CKM matrix element being close to unity. The aim of this paper is to show that off-diagonal couplings, like cb¯, may lead to substantial contributions to the cross section, even if the corresponding CKM matrix element is two orders of magnitude smaller. For this reason, the cross section is calculated for each initial state including all diagonal and off-diagonal terms, and all is finally added together to get the total cross section which is observed to be ∼2.7 times larger than what is obtained from cs¯ initial state. Results are eventually reflected into 95% C.L. exclusion and 5σ discovery contours at different integrated luminosities of LHC. A reasonable coverage of the parameter space is obtained by the 95% C.L. exclusion contour.

  7. Measurement of light charged particles in the decay channels of medium-mass excited compound nuclei

    Science.gov (United States)

    Valdré, S.; Barlini, S.; Casini, G.; Pasquali, G.; Piantelli, S.; Carboni, S.; Cinausero, M.; Gramegna, F.; Marchi, T.; Baiocco, G.; Bardelli, L.; Benzoni, G.; Bini, M.; Blasi, N.; Bracco, A.; Brambilla, S.; Bruno, M.; Camera, F.; Corsi, A.; Crespi, F.; D'Agostino, M.; Degerlier, M.; Kravchuk, V. L.; Leoni, S.; Million, B.; Montanari, D.; Morelli, L.; Nannini, A.; Nicolini, R.; Poggi, G.; Vannini, G.; Wieland, O.; Bednarczyk, P.; Ciemała, M.; Dudek, J.; Fornal, B.; Kmiecik, M.; Maj, A.; Matejska-Minda, M.; Mazurek, K.; Męczyński, W. M.; Myalski, S.; Styczeń, J.; Ziębliński, M.

    2014-03-01

    The 48Ti on 40Ca reactions have been studied at 300 and 600 MeV focusing on the fusion-evaporation (FE) and fusion-fission (FF) exit channels. Energy spectra and multiplicities of the emitted light charged particles have been compared to Monte Carlo simulations based on the statistical model. Indeed, in this mass region (A ~ 100) models predict that shape transitions can occur at high spin values and relatively scarce data exist in the literature about coincidence measurements between evaporation residues and light charged particles. Signals of shape transitions can be found in the variations of the lineshape of high energy gamma rays emitted from the de-excitation of GDR states gated on different region of angular momenta. For this purpose it is important to keep under control the FE and FF processes, to regulate the statistical model parameters and to control the onset of possible pre-equilibrium emissions from 300 to 600 MeV bombarding energy.

  8. Mathematical analysis of depolarization block mediated by slow inactivation of fast sodium channels in midbrain dopamine neurons.

    Science.gov (United States)

    Qian, Kun; Yu, Na; Tucker, Kristal R; Levitan, Edwin S; Canavier, Carmen C

    2014-12-01

    Dopamine neurons in freely moving rats often fire behaviorally relevant high-frequency bursts, but depolarization block limits the maximum steady firing rate of dopamine neurons in vitro to ∼10 Hz. Using a reduced model that faithfully reproduces the sodium current measured in these neurons, we show that adding an additional slow component of sodium channel inactivation, recently observed in these neurons, qualitatively changes in two different ways how the model enters into depolarization block. First, the slow time course of inactivation allows multiple spikes to be elicited during a strong depolarization prior to entry into depolarization block. Second, depolarization block occurs near or below the spike threshold, which ranges from -45 to -30 mV in vitro, because the additional slow component of inactivation negates the sodium window current. In the absence of the additional slow component of inactivation, this window current produces an N-shaped steady-state current-voltage (I-V) curve that prevents depolarization block in the experimentally observed voltage range near -40 mV. The time constant of recovery from slow inactivation during the interspike interval limits the maximum steady firing rate observed prior to entry into depolarization block. These qualitative features of the entry into depolarization block can be reversed experimentally by replacing the native sodium conductance with a virtual conductance lacking the slow component of inactivation. We show that the activation of NMDA and AMPA receptors can affect bursting and depolarization block in different ways, depending upon their relative contributions to depolarization versus to the total linear/nonlinear conductance.

  9. Sensory neuron-specific sodium channel SNS is abnormally expressed in the brains of mice with experimental allergic encephalomyelitis and humans with multiple sclerosis

    Science.gov (United States)

    Black, Joel A.; Dib-Hajj, Sulayman; Baker, David; Newcombe, Jia; Cuzner, M. Louise; Waxman, Stephen G.

    2000-10-01

    Clinical abnormalities in multiple sclerosis (MS) have classically been considered to be caused by demyelination and/or axonal degeneration; the possibility of molecular changes in neurons, such as the deployment of abnormal repertoires of ion channels that would alter neuronal electrogenic properties, has not been considered. Sensory Neuron-Specific sodium channel SNS displays a depolarized voltage dependence, slower activation and inactivation kinetics, and more rapid recovery from inactivation than classical "fast" sodium channels. SNS is selectively expressed in spinal sensory and trigeminal ganglion neurons within the peripheral nervous system and is not expressed within the normal brain. Here we show that sodium channel SNS mRNA and protein, which are not present within the cerebellum of control mice, are expressed within cerebellar Purkinje cells in a mouse model of MS, chronic relapsing experimental allergic encephalomyelitis. We also demonstrate SNS mRNA and protein expression within Purkinje cells from tissue obtained postmortem from patients with MS, but not in control subjects with no neurological disease. These results demonstrate a change in sodium channel expression in neurons within the brain in an animal model of MS and in humans with MS and suggest that abnormal patterns of neuronal ion channel expression may contribute to clinical abnormalities such as ataxia in these disorders.

  10. Neuroplastic alteration of TTX-resistant sodium channel with visceral pain and morphine-induced hyperalgesia

    Directory of Open Access Journals (Sweden)

    Chen J

    2012-11-01

    Full Text Available Jinghong Chen,1,2,4 Ze-hui Gong,4 Hao Yan,2 Zhijun Qiao,3 Bo-yi Qin41Department of Internal Medicine, Neuroscience Program, The University of Texas Medical Branch, Galveston, TX, USA; 2The Divisions of Pharmacy, Pharmacology core lab, MD Anderson Cancer Center, Houston, TX, USA; 3University of Texas-Pan American, Edinburg, TX, USA; 4Beijing Institute of Pharmacology and Toxicology, Beijing, China Abstract: The discovery of the tetrodotoxin-resistant (TTX-R Na+ channel in nociceptive neurons has provided a special target for analgesic intervention. In a previous study we found that both morphine tolerance and persistent visceral inflammation resulted in visceral hyperalgesia. It has also been suggested that hyperexcitability of sensory neurons due to altered TTX-R Na+ channel properties and expression contributes to hyperalgesia; however, we do not know if some TTX-R Na+ channel property changes can be triggered by visceral hyperalgesia and morphine tolerance, or whether there are similar molecular or channel mechanisms in both situations. To evaluate the effects of morphine tolerance and visceral inflammation on the channel, we investigated the dorsal root ganglia (DRG neuronal change following these chronic treatments. Using whole-cell patch clamp recording, we recorded TTX-R Na+ currents in isolated adult rat lumbar and sacral (L6-S2 DRG neurons from normal and pathologic rats with colon inflammatory pain or chronic morphine treatment. We found that the amplitudes of TTX-R Na+ currents were signiflcantly increased in small-diameter DRG neurons with either morphine tolerance or visceral inflammatory pain. Meanwhile, the result also showed that those treatments altered the kinetics properties of the electrical current (ie, the activating and inactivating speed of the channel was accelerated. Our current results suggested that in both models, visceral chronic inflammatory pain and morphine tolerance causes electrophysiological changes in voltage

  11. The structure of zetekitoxin AB, a saxitoxin analog from the Panamanian golden frog Atelopus zeteki: A potent sodium-channel blocker

    OpenAIRE

    Yotsu-Yamashita, Mari; Yong H Kim; Dudley, Samuel C.; Choudhary, Gaurav; Pfahnl, Arnold; Oshima, Yasukatsu; Daly, John W.

    2004-01-01

    Bufonid anurans of the genus Atelopus contain both steroidal bufadienolides and various guanidinium alkaloids of the tetrodotoxin class. The former inhibit sodium-potassium ATPases, whereas the latter block voltage-dependent sodium channels. The structure of one guanidinium alkaloid, zetekitoxin AB, has remained a mystery for over 30 years. The structure of this alkaloid now has been investigated with a sample of ≈0.3 mg, purified from extracts obtained decades ago from the Panamanian golden ...

  12. Sodium Channel Gene Mutations in Children with GEFS+ and Dravet Syndrome: A Cross Sectional Study

    Directory of Open Access Journals (Sweden)

    Seyed Hassan TONEKABONI

    2013-06-01

    Full Text Available  How to Cite This Article: Tonekaboni SH, Ebrahimi A, Bakhshandeh Bali MK, Houshmand M, Moghaddasi M, Taghdiri MM, Nasehi MM. Sodium Channel Gene Mutations in Children with GEFS+ and Dravet Syndrome: A Cross Sectional Study. Iran J Child Neurol. 2013 Winter; 7 (1:25-29. Objective Dravet syndrome or severe myoclonic epilepsy of infancy (SMEI is a baleful epileptic encephalopathy that begins in the first year of life. This syndrome specified by febrile seizures followed by intractable epilepsy, disturbed psychomotor development, and ataxia. Clinical similarities between Dravet syndrome and generalized epilepsy with febrile seizure plus (GEFS+ includes occurrence of febrile seizures and joint molecular genetic etiology. Shared features of these two diseases support the idea that these two disorders represent a severity spectrum of the same illness. Nowadays, more than 60 heterozygous pattern SCN1A mutations, which many are de novo mutations, have been detected in Dravet syndrome. Materials & Methods From May 2008 to August 2012, 35 patients who referred to Pediatric Neurology Clinic of Mofid Children Hospital in Tehran were enrolled in this study. Entrance criterion of this study was having equal or more than four criteria for Dravet syndrome. We compared clinical features and genetic findings of the patients diagnosed as Dravet syndrome or GEFS+. Results 35 patients (15 girls and 20 boys underwent genetic testing. Mean age of them was 7.7 years (a range of 13 months to 15 years. Three criteria that were best evident in SCN1A mutation positive patients are as follows: Normal development before the onset of seizures, onset of seizure before age of one year, and psychomotor retardation after onset of seizures. Our genetic testing showed that 1 of 3 (33.3% patients with clinical Dravet syndrome and 3 of 20 (15% patients that diagnosed as GEFS+, had SCN1A mutation. Conclusion In this study, normal development before seizure onset, seizures beginning

  13. Expression of hNav1.8 sodium channel protein in affected nerves of patients with trigeminal neuralgia

    Institute of Scientific and Technical Information of China (English)

    ZHU Ling-lan; JIANG Xiao-zhong; ZHAO Yun-fu; LI Yu-li; HE Jin

    2004-01-01

    Objective: To explore the pathogenesis of trigeminal neuralgia (TN) and to provide a new target for the drug treatment of TN by studying the expression of tetrodotoxin-resistant hNavl. 8 sodium channel protein in affected nerves of patients with TN. Methods: Twelve affected inferior alveolar nerves were obtained from patients with idiopathic TN, to whom the drug therapy was not effective. As negative control, one normal inferior alveolar nerve was obtained from patients who accepted the combined radical neck dissection with glossectomy and mandibulectomy. One muscle sample was obtained as normal control. One dorsal root ganglion from rat was as positive control. These tissues and prepared hNav1.8 antibody were conducted immunohistochemistry response. Results: hNavl. 8 channel protein was expresses in all the 12 specimens of the affected nerves of patients with TN, but not in the muscle sample and the normal inferior alveolar nerve. Conclusion:The abnormal expression of hNavl. 8 channel protein in the affected nerves of patients with TN may play an impo~nt role in the pathogenesis of TN.

  14. Fast Atomic Charge Calculation for Implementation into a Polarizable Force Field and Application to an Ion Channel Protein

    Directory of Open Access Journals (Sweden)

    Raiker Witter

    2015-01-01

    Full Text Available Polarization of atoms plays a substantial role in molecular interactions. Class I and II force fields mostly calculate with fixed atomic charges which can cause inadequate descriptions for highly charged molecules, for example, ion channels or metalloproteins. Changes in charge distributions can be included into molecular mechanics calculations by various methods. Here, we present a very fast computational quantum mechanical method, the Bond Polarization Theory (BPT. Atomic charges are obtained via a charge calculation method that depend on the 3D structure of the system in a similar way as atomic charges of ab initio calculations. Different methods of population analysis and charge calculation methods and their dependence on the basis set were investigated. A refined parameterization yielded excellent correlation of R=0.9967. The method was implemented in the force field COSMOS-NMR and applied to the histidine-tryptophan-complex of the transmembrane domain of the M2 protein channel of influenza A virus. Our calculations show that moderate changes of side chain torsion angle χ1 and small variations of χ2 of Trp-41 are necessary to switch from the inactivated into the activated state; and a rough two-side jump model of His-37 is supported for proton gating in accordance with a flipping mechanism.

  15. AMP-Activated Protein Kinase Attenuates High Salt-Induced Activation of Epithelial Sodium Channels (ENaC) in Human Umbilical Vein Endothelial Cells.

    Science.gov (United States)

    Zheng, Wei-Wan; Li, Xin-Yuan; Liu, Hui-Bin; Wang, Zi-Rui; Hu, Qing-Qing; Li, Yu-Xia; Song, Bin-Lin; Lou, Jie; Wang, Qiu-Shi; Ma, He-Ping; Zhang, Zhi-Ren

    2016-01-01

    Recent studies suggest that the epithelial sodium channel (ENaC) is expressed in the endothelial cells. To test whether high salt affects the NO production via regulation of endothelial ENaC, human umbilical vein endothelial cells (HUVECs) were incubated in solutions containing either normal or high sodium (additional 20 mM NaCl). Our data showed that high sodium treatment significantly increased α-, β-, and γ-ENaC expression levels in HUVECs. Using the cell-attached patch-clamp technique, we demonstrated that high sodium treatment significantly increased ENaC open probability (P O ). Moreover, nitric oxide synthase (eNOS) phosphorylation (Ser 1177) levels and NO production were significantly decreased by high sodium in HUVECs; the effects of high sodium on eNOS phosphorylation and NO production were inhibited by a specific ENaC blocker, amiloride. Our results showed that high sodium decreased AMP-activated kinase (AMPK) phosphorylation in endothelial cells. On the other hand, metformin, an AMPK activator, prevented high sodium-induced upregulation of ENaC expression and P O . Moreover, metformin prevented high salt-induced decrease in NO production and eNOS phosphorylation. These results suggest that high sodium stimulates ENaC activation by negatively modulating AMPK activity, thereby leading to reduction in eNOS activity and NO production in endothelial cells. PMID:27635187

  16. Inhibition of collagen synthesis by select calcium and sodium channel blockers can be mitigated by ascorbic acid and ascorbyl palmitate.

    Science.gov (United States)

    Ivanov, Vadim; Ivanova, Svetlana; Kalinovsky, Tatiana; Niedzwiecki, Aleksandra; Rath, Matthias

    2016-01-01

    Calcium, sodium and potassium channel blockers are widely prescribed medications for a variety of health problems, most frequently for cardiac arrhythmias, hypertension, angina pectoris and other disorders. However, chronic application of channel blockers is associated with numerous side effects, including worsening cardiac pathology. For example, nifedipine, a calcium-channel blocker was found to be associated with increased mortality and increased risk for myocardial infarction. In addition to the side effects mentioned above by different channel blockers, these drugs can cause arterial wall damage, thereby contributing to vascular wall structure destabilization and promoting events facilitating rupture of plaques. Collagen synthesis is regulated by ascorbic acid, which is also essential for its optimum structure as a cofactor in lysine and proline hydroxylation, a precondition for optimum crosslinking of collagen and elastin. Therefore, the main objective in this study was to evaluate effects of various types of channel blockers on intracellular accumulation and cellular functions of ascorbate, specifically in relation to formation and extracellular deposition of major collagen types relevant for vascular function. Effects of select Na- and Ca- channel blockers on collagen synthesis and deposition were evaluated in cultured human dermal fibroblasts and aortic smooth muscle cells by immunoassay. All channel blockers tested demonstrated inhibitory effects on collagen type I deposition to the ECM by fibroblasts, each to a different degree. Ascorbic acid significantly increased collagen I ECM deposition. Nifedipine (50 µM), a representative of channel blockers tested, significantly reduced ascorbic acid and ascorbyl palmitate-dependent ECM deposition of collagen type l and collagen type lV by cultured aortic smooth muscle cells. In addition, nifedipine (50 µM) significantly reduced ascorbate-dependent collagen type l and type lV synthesis by cultured aortic smooth

  17. Topographical localization of the C-terminal region of the voltage-dependent sodium channel from Electrophorus electricus using antibodies raised against a synthetic peptide

    Energy Technology Data Exchange (ETDEWEB)

    Gordon, R.D.; Fieles, W.E.; Schotland, D.L.; Hogue-Angeletti, R.; Barchi, R.L.

    1987-01-01

    A peptide corresponding to amino acid residues 1783-1794 near the C terminus of the electric eel sodium channel primary sequence of the eel (Electrophorus electricus) sodium channel has been synthesized and used to raise an antiserum in rabbits. This antiserum specifically recognized the peptide in a solid-phase radioimmunoassay. Specificity of the antiserum for the native channel protein was shown by its specific binding to a 280-kDa protein in immunoblots of eel electroplax membrane proteins. The antiserum also specifically labeled the innervated membrane of the eel electroplax in immunofluorescent studies. The membrane topology of the peptide recognized by this antiserum was proved in binding studies using oriented electroplax membrane vesicles. These vesicles were 98% right-side-out as determined by (/sup 3/H)saxitoxin binding. Binding of the antipeptide antiserum to this fraction was measured before and after permeabilization with 0.01% saponin. Specific binding to intact vesicles was low, but this binding increased 10-fold after permeabilization, implying a cytoplasmic orientation for the peptide. Confirmation for this orientation was then sought by localizing the antibody bound to intact electroplax cells with immunogold electron microscopy. The data imply that the region of the sodium channel primary sequence near the C terminus that is recognized by the anitserum is localized on the cytoplasmic side of the membrane; this localization provides some further constraints on models of sodium channel tertiary structure.

  18. Topographical localization of the C-terminal region of the voltage-dependent sodium channel from Electrophorus electricus using antibodies raised against a synthetic peptide

    International Nuclear Information System (INIS)

    A peptide corresponding to amino acid residues 1783-1794 near the C terminus of the electric eel sodium channel primary sequence of the eel (Electrophorus electricus) sodium channel has been synthesized and used to raise an antiserum in rabbits. This antiserum specifically recognized the peptide in a solid-phase radioimmunoassay. Specificity of the antiserum for the native channel protein was shown by its specific binding to a 280-kDa protein in immunoblots of eel electroplax membrane proteins. The antiserum also specifically labeled the innervated membrane of the eel electroplax in immunofluorescent studies. The membrane topology of the peptide recognized by this antiserum was proved in binding studies using oriented electroplax membrane vesicles. These vesicles were 98% right-side-out as determined by [3H]saxitoxin binding. Binding of the antipeptide antiserum to this fraction was measured before and after permeabilization with 0.01% saponin. Specific binding to intact vesicles was low, but this binding increased 10-fold after permeabilization, implying a cytoplasmic orientation for the peptide. Confirmation for this orientation was then sought by localizing the antibody bound to intact electroplax cells with immunogold electron microscopy. The data imply that the region of the sodium channel primary sequence near the C terminus that is recognized by the anitserum is localized on the cytoplasmic side of the membrane; this localization provides some further constraints on models of sodium channel tertiary structure

  19. Co-Localization of Sodium Channel Na[v]1.6 and the Sodium--Calcium Exchanger at Sites of Axonal Injury in the Spinal Cord in EAE

    Science.gov (United States)

    Craner, Matthew J.; Hains, Bryan C.; Lo, Albert C.; Black, Joel A.; Waxman, Stephen G.

    2004-01-01

    Axonal degeneration contributes to the development of non-remitting neurological deficits and disability in multiple sclerosis, but the molecular mechanisms that underlie axonal loss in multiple sclerosis are not clearly understood. Studies of white matter axonal injury have demonstrated that voltage-gated sodium channels can provide a route for…

  20. Molecular determinant for the tarantula toxin Jingzhaotoxin-I slowing the fast inactivation of voltage-gated sodium channels.

    Science.gov (United States)

    Tao, Huai; Chen, Xia; Lu, Min; Wu, Yuanyuan; Deng, Meichun; Zeng, Xiongzhi; Liu, Zhonghua; Liang, Songping

    2016-03-01

    Peptide toxins often have divergent pharmacological functions and are powerful tools for a deep review on the current understanding of the structure-function relationships of voltage-gated sodium channels (VGSCs). However, knowing about the interaction of site 3 toxins from tarantula venoms with VGSCs is not sufficient. In the present study, using whole-cell patch clamp technique, we determined the effects of Jingzhaotoxin-I (JZTX-I) on five VGSC subtypes expressed in HEK293 cells. The results showed that JZTX-I could inhibit the inactivation of rNav1.2, rNav1.3, rNav1.4, hNav1.5 and hNav1.7 channels with the IC50 of 870 ± 8 nM, 845 ± 4 nM, 339 ± 5 nM, 335 ± 9 nM, and 348 ± 6 nM, respectively. The affinity of the toxin interaction with subtypes (rNav1.4, hNav1.5, and hNav1.7) was only 2-fold higher than that for subtypes (rNav1.2 and rNav1.3). The toxin delayed the inactivation of VGSCs without affecting the activation and steady-state inactivation kinetics in the physiological range of voltages. Site-directed mutagenesis indicated that the toxin interacted with site 3 located at the extracellular S3-S4 linker of domain IV, and the acidic residue Asp at the position1609 in hNav1.5 was crucial for JZTX-I activity. Our results provide new insights in single key residue that allows toxins to recognize distinct ion channels with similar potency and enhance our understanding of the structure-function relationships of toxin-channel interactions. PMID:26721415

  1. Divergent actions of the pyrethroid insecticides S-bioallethrin, tefluthrin, and deltamethrin on rat Na(v)1.6 sodium channels.

    Science.gov (United States)

    Tan, Jianguo; Soderlund, David M

    2010-09-15

    We expressed rat Na(v)1.6 sodium channels in combination with the rat beta(1) and beta(2) auxiliary subunits in Xenopus laevis oocytes and evaluated the effects of the pyrethroid insecticides S-bioallethrin, deltamethrin, and tefluthrin on expressed sodium currents using the two-electrode voltage clamp technique. S-Bioallethrin, a type I structure, produced transient modification evident in the induction of rapidly decaying sodium tail currents, weak resting modification (5.7% modification at 100 microM), and no further enhancement of modification upon repetitive activation by high-frequency trains of depolarizing pulses. By contrast deltamethrin, a type II structure, produced sodium tail currents that were ~9-fold more persistent than those caused by S-bioallethrin, barely detectable resting modification (2.5% modification at 100 microM), and 3.7-fold enhancement of modification upon repetitive activation. Tefluthrin, a type I structure with high mammalian toxicity, exhibited properties intermediate between S-bioallethrin and deltamethrin: intermediate tail current decay kinetics, much greater resting modification (14.1% at 100 microM), and 2.8-fold enhancement of resting modification upon repetitive activation. Comparison of concentration-effect data showed that repetitive depolarization increased the potency of tefluthrin approximately 15-fold and that tefluthrin was approximately 10-fold more potent than deltamethrin as a use-dependent modifier of Na(v)1.6 sodium channels. Concentration-effect data from parallel experiments with the rat Na(v)1.2 sodium channel coexpressed with the rat beta(1) and beta(2) subunits in oocytes showed that the Na(v)1.6 isoform was at least 15-fold more sensitive to tefluthrin and deltamethrin than the Na(v)1.2 isoform. These results implicate sodium channels containing the Na(v)1.6 isoform as potential targets for the central neurotoxic effects of pyrethroids.

  2. The structure of zetekitoxin AB, a saxitoxin analog from the Panamanian golden frog Atelopus zeteki: a potent sodium-channel blocker.

    Science.gov (United States)

    Yotsu-Yamashita, Mari; Kim, Yong H; Dudley, Samuel C; Choudhary, Gaurav; Pfahnl, Arnold; Oshima, Yasukatsu; Daly, John W

    2004-03-30

    Bufonid anurans of the genus Atelopus contain both steroidal bufadienolides and various guanidinium alkaloids of the tetrodotoxin class. The former inhibit sodium-potassium ATPases, whereas the latter block voltage-dependent sodium channels. The structure of one guanidinium alkaloid, zetekitoxin AB, has remained a mystery for over 30 years. The structure of this alkaloid now has been investigated with a sample of approximately 0.3 mg, purified from extracts obtained decades ago from the Panamanian golden frog Atelopus zeteki. Detailed NMR and mass spectral analyses have provided the structure and relative stereochemistry of zetekitoxin AB and have revealed that it is an analog of saxitoxin. The proposed structure is characterized by richness of heteroatoms (C16H25N8O12S) and contains a unique 1,2-oxazolidine ring-fused lactam, a sulfate ester, and an N-hydroxycarbamate moiety. Zetekitoxin AB proved to be an extremely potent blocker of voltage-dependent sodium channels expressed in Xenopus oocytes. The IC50 values were 280 pM for human heart channels, 6.1 pM for rat brain IIa channels, and 65 pM for rat skeletal muscle channels, thus being roughly 580-, 160-, and 63-fold more potent at these channels than saxitoxin. PMID:15070720

  3. Identification of a cluster of residues in transmembrane segment 6 of domain III of the cockroach sodium channel essential for the action of pyrethroid insecticides.

    Science.gov (United States)

    Du, Yuzhe; Lee, Jung-Eun; Nomura, Yoshiko; Zhang, Tianxiang; Zhorov, Boris S; Dong, Ke

    2009-04-15

    A phenylalanine residue (Phe1519) in the sixth transmembrane segment of domain III (IIIS6) of the cockroach BgNa(v) sodium channel is required for the binding and action of pyrethroids. However, whether or not other residues in IIIS6 participate in the action of pyrethroids remains to be determined. In the present study, we conducted a systematic analysis of 20 residues in IIIS6 of the BgNa(v) channel using alanine-scanning mutagenesis. Our results show that alanine substitutions of four residues, Ile1514, Gly1516, Phe1518 and Asn1522, altered sodium channel sensitivity to pyrethroid insecticides. Whereas the G1516A, F1518A and N1522A substitutions diminished sodium channel sensitivity to all seven pyrethroids examined, including four type I (lacking the alpha-cyano group at the phenoxybenzyl alcohol) and three type II (containing the alpha-cyano group) pyrethroids, the I1514A substitution enhanced sodium channel sensitivity to four type I and type II pyrethroids that contain the phenoxybenzyl alcohol only. We also show that alanine/lysine substitutions of Leu1521 and Ser1517 affected the action of BTX (batrachotoxin), but not pyrethroids. In the Kv1.2-based homology model of the open sodium channel, side chains of Ile1514, Phe1518 and Asn1522 are exposed towards helix IIS5 and linker IIS4-IIS5, which contain previously identified pyrethroid-interacting residues, whereas Ser1517 and Leu1521 face the inner pore where the BTX receptor is located. Thus the present study provides further evidence for structural models in which pyrethroids bind to the lipid-exposed interface formed by helices IIIS6, IIS5 and linker helix IIS4-IIS5, whereas BTX binds to the pore-exposed side of the IIIS6 helix.

  4. Functional interaction between S1 and S4 segments in voltage-gated sodium channels revealed by human channelopathies.

    Science.gov (United States)

    Amarouch, Mohamed-Yassine; Kasimova, Marina A; Tarek, Mounir; Abriel, Hugues

    2014-01-01

    The p.I141V mutation of the voltage-gated sodium channel is associated with several clinical hyper-excitability phenotypes. To understand the structural bases of the p.I141V biophysical alterations, molecular dynamics simulations were performed. These simulations predicted that the p.I141V substitution induces the formation of a hydrogen bond between the Y168 residue of the S2 segment and the R225 residue of the S4 segment. We generated a p.I141V-Y168F double mutant for both the Nav1.4 and Nav1.5 channels. The double mutants demonstrated the abolition of the functional effects of the p.I141V mutation, consistent with the formation of a specific interaction between Y168-S2 and R225-S4. The single p.Y168F mutation, however, positively shifted the activation curve, suggesting a compensatory role of these residues on the stability of the voltage-sensing domain.

  5. THE PRESENCE OF A B SUBUNIT INCREASES SENSITIVITY OF SODIUM CHANNEL NAV1.3, BUT NOT NAV1.2, TO TYPE II PYRETHROIDS.

    Science.gov (United States)

    Voltage-sensitive sodium channels (VSSCs) are a primary target of pyrethroid insecticides. VSSCs are comprised of a pore-forming ¿ and auxillary ß subunits, and multiple isoforms of both subunit types exist. The sensitivity of different isoform combinations to pyrethroids has not...

  6. Point mutations at the local anesthetic receptor site modulate the state-dependent block of rat Na v1.4 sodium channels by pyrazoline-type insecticides.

    Science.gov (United States)

    Silver, Kristopher S; Soderlund, David M

    2007-05-01

    Pyrazoline-type insecticides (PTIs) selectively block sodium channels at membrane potentials that promote slow sodium channel inactivation and are proposed to interact with a site that overlaps the local anesthetic (LA) receptor site. Mutagenesis studies identified two amino acid residues in the S6 segment of homology domain IV (Phe-1579 and Tyr-1586 in the rat Na(v)1.4 sodium channel) as principal elements of the LA receptor. To test the hypothesis that PTIs bind to the LA receptor, we constructed mutated Na(v)1.4/F1579A and Na(v)1.4/Y1586A cDNAs, expressed native and mutated channels in Xenopus oocytes, and examined the effects of these mutations on channel block by three PTIs (indoxacarb, its bioactivation product DCJW, and RH3421) by two-electrode voltage clamp. DCJW and RH3421 had no effect on Na(v)1.4 channels held at -120mV but caused a slowly developing block upon depolarization to -30mV. Estimated IC(50) values following 15min of exposure were 1 and 4muM for DCJW and RH3421, respectively. Indoxacarb failed to block Na(v)1.4 channels under all experimental conditions. Sensitivity to block by DCJW and RH3421 at -30mV was significantly reduced in Na(v)1.4/F1579A channels, a finding that is consistent with the impact of this mutation on drug binding. In contrast to its effect on drug binding, the Y1586A mutation increased the sensitivity of Na(v)1.4 channels held at -30mV to all three compounds, conferring modest sensitivity to indoxacarb and increasing sensitivity to DCJW and RH3421 by 58- and 16-fold, respectively. These results provide direct evidence for the action of PTIs at the LA receptor.

  7. Sodium channel gating in clonal pituitary cells. The inactivation step is not voltage dependent

    OpenAIRE

    1989-01-01

    We have determined the time course of Na channel inactivation in clonal pituitary (GH3) cells by comparing records before and after the enzymatic removal of inactivation. The cells were subjected to whole- cell patch clamp, with papain included in the internal medium. Inactivation was slowly removed over the course of 10 min, making it possible to obtain control records before the enzyme acted. Papain caused a large (4-100x) increase in current magnitude for small depolarizations (near -40 mV...

  8. Sodium channel mutation in irritable bowel syndrome: evidence for an ion channelopathy

    OpenAIRE

    Saito, Yuri A; Strege, Peter R.; Tester, David J.; Locke, G. Richard; Talley, Nicholas J; Bernard, Cheryl E.; Rae, James L.; Makielski, Jonathan C.; Ackerman, Michael J.; Farrugia, Gianrico

    2008-01-01

    The SCN5A-encoded Nav1.5 Na+ channel is expressed in interstitial cells of Cajal and smooth muscle in the circular layer of the human intestine. Patients with mutations in SCN5A are more likely to report gastrointestinal symptoms, especially abdominal pain. Twin and family studies of irritable bowel syndrome (IBS) suggest a genetic basis for IBS, but no genes have been identified to date. Therefore, our aims were to evaluate SCN5A as a candidate gene involved in the pathogenesis of IBS and to...

  9. Inhibition of nitrite-induced toxicity in channel catfish by calcium chloride and sodium chloride

    Science.gov (United States)

    Tommasso J.R., Wright; Simco, B.A.; Davis, K.B.

    1980-01-01

    Environmental chloride has been shown to inhibit methemoglobin formation in fish, thereby offering a protective effect against nitrite toxicity. Channel catfish (Ictalurus punctatus) were simultaneously exposed to various environmental nitrite and chloride levels (as either CaCl2 or NaCl) in dechlorinated tap water (40 mg/L total hardness, 47 mg/L alkalinity, 4 mg/L chloride, pH = 6.9-7.1, and temperature 21-24°C). Methemoglobin levels in fish simultaneously exposed to 2.5 mg/L nitrite and up to 30 mg/L chloride as either CaCl2 or NaCl were similar but significantly lower than in unprotected fish. Exposure to 10 mg/L nitrite and 60 mg/L chloride resulted in methemoglobin levels similar to those of the controls; most unprotected fish died. Fish exposed to 10 mg/L nitrite had significantly lower methemoglobin levels when protected with 15.0 mg/L chloride as CaCl2 than with NaCl. Fish exposed to nitrite in the presence of 60 mg/L chloride (as either CaCl2 or NaCl) had similar 24-h LC50 values that were significantly elevated above those obtained in the absence of chloride. Calcium had little effect on tolerance to nitrite toxicity in channel catfish in contrast to its large effect reported in steelhead trout (Salmo gairdneri).

  10. Crystal Structure of a Fibroblast Growth Factor Homologous Factor (FHF) Defines a Conserved Surface on FHFs for Binding and Modulation of Voltage-gated Sodium Channels

    Energy Technology Data Exchange (ETDEWEB)

    Goetz, R.; Dover, K; Laezza, F; Shtraizent, N; Huang, X; Tchetchik, D; Eliseenkova, A; Goldfarb, M; Mohammadi, M; et. al.

    2009-01-01

    Voltage-gated sodium channels (Nav) produce sodium currents that underlie the initiation and propagation of action potentials in nerve and muscle cells. Fibroblast growth factor homologous factors (FHFs) bind to the intracellular C-terminal region of the Nav alpha subunit to modulate fast inactivation of the channel. In this study we solved the crystal structure of a 149-residue-long fragment of human FHF2A which unveils the structural features of the homology core domain of all 10 human FHF isoforms. Through analysis of crystal packing contacts and site-directed mutagenesis experiments we identified a conserved surface on the FHF core domain that mediates channel binding in vitro and in vivo. Mutations at this channel binding surface impaired the ability of FHFs to co-localize with Navs at the axon initial segment of hippocampal neurons. The mutations also disabled FHF modulation of voltage-dependent fast inactivation of sodium channels in neuronal cells. Based on our data, we propose that FHFs constitute auxiliary subunits for Navs.

  11. A sodium channel inhibitor ISTX-I with a novel structure provides a new hint at the evolutionary link between two toxin folds.

    Science.gov (United States)

    Rong, Mingqiang; Liu, Jiangxin; Zhang, Meilin; Wang, Gan; Zhao, Gang; Wang, Guodong; Zhang, Yaping; Hu, Kaifeng; Lai, Ren

    2016-01-01

    Members of arachnida, such as spiders and scorpions, commonly produce venom with specialized venom glands, paralyzing their prey with neurotoxins that specifically target ion channels. Two well-studied motifs, the disulfide-directed hairpin (DDH) and the inhibitor cystine knot motif (ICK), are both found in scorpion and spider toxins. As arachnids, ticks inject a neurotoxin-containing cocktail from their salivary glands into the host to acquire a blood meal, but peptide toxins acting on ion channels have not been observed in ticks. Here, a new neurotoxin (ISTX-I) that acts on sodium channels was identified from the hard tick Ixodes scapularis and characterized. ISTX-I exhibits a potent inhibitory function with an IC50 of 1.6 μM for sodium channel Nav1.7 but not other sodium channel subtypes. ISTX-I adopts a novel structural fold and is distinct from the canonical ICK motif. Analysis of the ISTX-I, DDH and ICK motifs reveals that the new ISTX-I motif might be an intermediate scaffold between DDH and ICK, and ISTX-I is a clue to the evolutionary link between the DDH and ICK motifs. These results provide a glimpse into the convergent evolution of neurotoxins from predatory and blood-sucking arthropods. PMID:27407029

  12. A sodium channel inhibitor ISTX-I with a novel structure provides a new hint at the evolutionary link between two toxin folds

    Science.gov (United States)

    Rong, Mingqiang; Liu, Jiangxin; Zhang, Meilin; Wang, Gan; Zhao, Gang; Wang, Guodong; Zhang, Yaping; Hu, Kaifeng; Lai, Ren

    2016-01-01

    Members of arachnida, such as spiders and scorpions, commonly produce venom with specialized venom glands, paralyzing their prey with neurotoxins that specifically target ion channels. Two well-studied motifs, the disulfide-directed hairpin (DDH) and the inhibitor cystine knot motif (ICK), are both found in scorpion and spider toxins. As arachnids, ticks inject a neurotoxin-containing cocktail from their salivary glands into the host to acquire a blood meal, but peptide toxins acting on ion channels have not been observed in ticks. Here, a new neurotoxin (ISTX-I) that acts on sodium channels was identified from the hard tick Ixodes scapularis and characterized. ISTX-I exhibits a potent inhibitory function with an IC50 of 1.6 μM for sodium channel Nav1.7 but not other sodium channel subtypes. ISTX-I adopts a novel structural fold and is distinct from the canonical ICK motif. Analysis of the ISTX-I, DDH and ICK motifs reveals that the new ISTX-I motif might be an intermediate scaffold between DDH and ICK, and ISTX-I is a clue to the evolutionary link between the DDH and ICK motifs. These results provide a glimpse into the convergent evolution of neurotoxins from predatory and blood-sucking arthropods. PMID:27407029

  13. Human neocortical excitability is decreased during anoxia via sodium channel modulation.

    Science.gov (United States)

    Cummins, T R; Jiang, C; Haddad, G G

    1993-02-01

    When the central nervous system in humans is deprived of oxygen, the effects are potentially disastrous. Electroencephalographic activity is lost and higher brain function ceases rapidly. Despite the importance of these effects, the mechanisms underlying the loss of cortical activity are poorly understood. Using intracellular recordings of human neocortical neurons in tissue slices, we show that, whereas anoxia produces a relatively small depolarization and modest alterations in passive properties, it causes a major decrease in excitability. Whole-cell voltage-clamp studies of acutely isolated human neocortical pyramidal neurons demonstrate that anoxia and metabolic inhibition produce a large negative shift in the steady-state inactivation [h infinity (V)] curve for the voltage-dependent sodium current (INa). Inclusion of ATP in the patch pipette decreased the shift of the h infinity (V) curve by two-thirds. Because increased inactivation of INa decreases cellular metabolic demand, we postulate that this promotes neuronal survival during periods of oxygen deprivation. These data show a novel mechanism by which anoxia links metabolism to membrane ionic conductances in human cortical neurons. PMID:8381823

  14. Regulation of sodium channel function by bilayer elasticity: the importance of hydrophobic coupling. Effects of Micelle-forming amphiphiles and cholesterol

    DEFF Research Database (Denmark)

    Lundbæk, Jens August; Birn, Pia; Hansen, Anker J;

    2004-01-01

    kinetics of the protein conformational changes therefore will be regulated by the bilayer elasticity, which is determined by the lipid composition. This hydrophobic coupling mechanism has been studied extensively in gramicidin channels, where the channel-bilayer hydrophobic interactions link a...... "conformational" change (the monomerdimer transition) to an elastic bilayer deformation. Gramicidin channels thus are regulated by the lipid bilayer elastic properties (thickness, monolayer equilibrium curvature, and compression and bending moduli). To investigate whether this hydrophobic coupling mechanism could...... be a general mechanism regulating membrane protein function, we examined whether voltage-dependent skeletal-muscle sodium channels, expressed in HEK293 cells, are regulated by bilayer elasticity, as monitored using gramicidin A (gA) channels. Nonphysiological amphiphiles (beta...

  15. Brevenal, a brevetoxin antagonist from Karenia brevis, binds to a previously unreported site on mammalian sodium channels.

    Science.gov (United States)

    Gold, Elena P; Jacocks, Henry M; Bourdelais, Andrea J; Baden, Daniel G

    2013-06-01

    Brevetoxins are a family of ladder-frame polyether toxins produced by the marine dinoflagellate Karenia brevis. During blooms of K. brevis, inhalation of brevetoxins aerosolized by wind and wave action can lead to asthma-like symptoms in persons at the beach. Consumption of either shellfish or finfish contaminated by K. brevis blooms can lead to the development of neurotoxic shellfish poisoning. The toxic effects of brevetoxins are due to binding at a defined site on, and subsequent activation of, voltage-sensitive sodium channels (VSSCs) in cell membranes (site 5). In addition to brevetoxins, K. brevis produces several other ladder-frame compounds. One of these compounds, brevenal, has been shown to antagonize the effects of brevetoxin. In an effort to further characterize to effects of brevenal, a radioactive analog ([(3)H]-brevenol) was produced by reducing the side-chain terminal aldehyde moiety of brevenal to an alcohol using tritiated sodium borohydride. A KD of 67 nM and Bmax of 7.1 pmol/mg protein were obtained for [(3)H]-brevenol in rat brain synaptosomes, suggesting a 1:1 matching with VSSCs. Brevenal and brevenol competed for [(3)H]-brevenol binding with Ki values of 75 nM and 56 nM, respectively. However, although both brevenal and brevenol can inhibit brevetoxin binding, brevetoxin was completely ineffective at competition for [(3)H]-brevenol binding. After examining other site-specific compounds, it was determined that [(3)H]-brevenol binds to a site that is distinct from the other known sites including the brevetoxin site (site 5) although some interaction with site 5 is apparent. PMID:23789024

  16. Effects of Amiodarone and N-Desethylamiodarone on Cardiac Voltage-gated Sodium Channels

    Directory of Open Access Journals (Sweden)

    Mohammad-Reza eGhovanloo

    2016-03-01

    Full Text Available Amiodarone (AMD is a potent antiarrhythmic drug with high efficacy for treating atrial fibrillation and tachycardia. The pharmacologic profile of AMD is complex. AMD possesses biophysical characteristics of all of class I, II, III, and IV agents. Despite its adverse side effects, AMD remains the most commonly prescribed antiarrhythmic drug. AMD was described to prolong the QT interval and can lead to torsades de pointes. Our goal was to study the effects of AMD on peak and late sodium currents (INa,P and INa,L and determine whether these effects change as AMD is metabolized into N-Desethylamiodarone (DES. We hypothesized that AMD and DES block both INa,P and INa,L with similar profiles due to structural similarities. Given the inherent small amounts of INa,L in NaV1.5, we screened AMD and DES against the Long QT-3-causing mutation, ∆KPQ, to better detect any drug-mediated effect on INa,L. Our results show that AMD and DES do not affect WT or ∆KPQ activation; however, both drugs altered the apparent valence of steady-state fast-inactivation. In addition, AMD and DES preferentially block ∆KPQ peak conductance compared to WT. Both compounds significantly increase INa,L and window currents. We conclude that both compounds have pro-arrhythmic effects on NaV1.5, especially ∆KPQ; however, DES seems to have a greater pro-arrhythmic effect than AMD.

  17. Acetylation stimulates the epithelial sodium channel by reducing its ubiquitination and degradation.

    Science.gov (United States)

    Butler, Phillip L; Staruschenko, Alexander; Snyder, Peter M

    2015-05-15

    The epithelial Na(+) channel (ENaC) functions as a pathway for Na(+) absorption in the kidney and lung, where it is crucial for Na(+) homeostasis and blood pressure regulation. ENaC is regulated in part through signaling pathways that control the ubiquitination state of ENaC lysines. A defect in ubiquitination causes Liddle syndrome, an inherited form of hypertension. Here we determined that α-, β-, and γENaC are also substrates for lysine acetylation. Trichostatin A (TSA), a histone deacetylase inhibitor, enhanced ENaC acetylation and increased ENaC abundance in the total cell lysate and at the cell surface. Moreover, TSA increased ENaC current in Fischer rat thyroid and kidney collecting duct epithelia. We found that HDAC7 is expressed in the kidney collecting duct, supporting a potential role for this histone deacetylase in ENaC regulation. HDAC7 overexpression reduced ENaC abundance and ENaC current, whereas ENaC abundance and current were increased by silencing of HDAC7. ENaC and HDAC7 form a complex, as detected by coimmunoprecipitation. We observed a reciprocal relationship between acetylation and ubiquitination; TSA reduced ENaC ubiquitination, whereas HDAC7 increased ubiquitination. By reducing ENaC ubiquitination, TSA decreased the rate of ENaC degradation. Thus, acetylation increases epithelial Na(+) absorption by antagonizing ENaC ubiquitination. This stabilizes ENaC, and hence, increases its abundance at the cell surface. PMID:25787079

  18. A New Poisson-Nernst-Planck Model with Ion-Water Interactions for Charge Transport in Ion Channels.

    Science.gov (United States)

    Chen, Duan

    2016-08-01

    In this work, we propose a new Poisson-Nernst-Planck (PNP) model with ion-water interactions for biological charge transport in ion channels. Due to narrow geometries of these membrane proteins, ion-water interaction is critical for both dielectric property of water molecules in channel pore and transport dynamics of mobile ions. We model the ion-water interaction energy based on realistic experimental observations in an efficient mean-field approach. Variation of a total energy functional of the biological system yields a new PNP-type continuum model. Numerical simulations show that the proposed model with ion-water interaction energy has the new features that quantitatively describe dielectric properties of water molecules in narrow pores and are possible to model the selectivity of some ion channels.

  19. A biomimetic DNA-based channel for the ligand-controlled transport of charged molecular cargo across a biological membrane

    Science.gov (United States)

    Burns, Jonathan R.; Seifert, Astrid; Fertig, Niels; Howorka, Stefan

    2016-02-01

    Biological ion channels are molecular gatekeepers that control transport across cell membranes. Recreating the functional principle of such systems and extending it beyond physiological ionic cargo is both scientifically exciting and technologically relevant to sensing or drug release. However, fabricating synthetic channels with a predictable structure remains a significant challenge. Here, we use DNA as a building material to create an atomistically determined molecular valve that can control when and which cargo is transported across a bilayer. The valve, which is made from seven concatenated DNA strands, can bind a specific ligand and, in response, undergo a nanomechanical change to open up the membrane-spanning channel. It is also able to distinguish with high selectivity the transport of small organic molecules that differ by the presence of a positively or negatively charged group. The DNA device could be used for controlled drug release and the building of synthetic cell-like or logic ionic networks.

  20. Cardiac Expression of Skeletal Muscle Sodium Channels Increases Longitudinal Conduction Velocity in the Canine One Week Myocardial Infarction

    Science.gov (United States)

    Coronel, Ruben; Lau, David H; Sosunov, Eugene A; Janse, Michiel J; Danilo, Peter; Anyukhovsky, Evgeny P; Wilms-Schopman, Francien JG; Opthof, Tobias; Shlapakova, Iryna N; Ozgen, Nazira; Prestia, Kevin; Kryukova, Yelena; Cohen, Ira S.; Robinson, Richard B; Rosen, Michael R

    2013-01-01

    Background Skeletal muscle sodium channel (Nav1.4) expression in border zone myocardium increases action potential upstroke velocity in depolarized isolated tissue. Because resting membrane potential in the 1 week canine infarct is reduced, we hypothesized that conduction velocity (CV) is greater in Nav1.4 dogs compared to control dogs. Objective To measure CV in the infarct border zone border in dogs with and without Nav1.4 expression. Methods Adenovirus was injected in the infarct border zone in 34 dogs. The adenovirus incorporated the Nav1.4- and a green fluorescent protein (GFP) gene (Nav1.4 group, n=16) or only GFP (n=18). After 1 week, upstroke velocity and CV were measured by sequential microelectrode recordings at 4 and 7 mM [K+] in superfused epicardial slabs. High density in vivo epicardial activation mapping was performed in a subgroup (8 Nav1.4, 6 GFP) at 3–4 locations in the border zone. Microscopy and antibody staining confirmed GFP or Nav1.4 expression. Results Infarct sizes were similar between groups (30.6+/−3 % of LV mass, mean+/−SEM). Longitudinal CV was greater in Nav1.4- than in GFP- sites (58.5+/−1.8 vs 53.3+/−1.2 cm/s, 20 and 15 sites, respectively, p<0.05). Transverse CV was not different between the groups. In tissue slabs dV/dtmax was higher and CV was greater in Nav1.4 than in control at 7 mM [K+] (P<0.05). Immunohistochemical Nav1.4 staining was seen at the longitudinal ends of the myocytes. Conclusion Nav1.4 channels in myocardium surviving 1 week infarction increases longitudinal but not transverse CV, consistent with the increased dV/dtmax and with the cellular localization of Nav1.4. PMID:20385252

  1. Functional and molecular characterization of voltage-gated sodium channels in uteri from nonpregnant rats.

    Science.gov (United States)

    Seda, Marian; Pinto, Francisco M; Wray, Susan; Cintado, Cristina G; Noheda, Pedro; Buschmann, Helmut; Candenas, Luz

    2007-11-01

    We investigated the function and expression of voltage-gated Na(+) channels (VGSC) in the uteri of nonpregnant rats using organ bath techniques, intracellular [Ca(2+)] fluorescence measurements, and RT-PCR. In longitudinally arranged whole-tissue uterine strips, veratridine, a VGSC activator, caused the rapid appearance of phasic contractions of irregular frequency and amplitude. After 50-60 min in the continuous presence of veratridine, rhythmic contractions of very regular frequency and slightly increasing amplitude occurred and were sustained for up to 12 h. Both the early and late components of the contractile response to veratridine were inhibited in a concentration-dependent manner by tetrodotoxin (TTX). In small strips dissected from the uterine longitudinal smooth muscle layer and loaded with Fura-2, veratridine also caused rhythmic contractions, accompanied by transient increases in [Ca(2+)](i), which were abolished by treatment with 0.1 microM TTX. Using end-point and real-time quantitative RT-PCR, we detected the presence of the VGSC alpha subunits Scn2a1, Scn3a, Scn5a, and Scn8a in the cDNA from longitudinal muscle. The mRNAs of the auxiliary beta subunits Scbn1b, Scbn2b, Scbn4b, and traces of Scn3b were also present. These data show for the first time that Scn2a1, Scn3a, Scn5a, and Scn8a, as well as all VGSC beta subunits are expressed in the longitudinal smooth muscle layer of the rat myometrium. In addition, our data show that TTX-sensitive VGSC are able to mediate phasic contractions maintained over long periods of time in the uteri of nonpregnant rats.

  2. Functional Expression of Voltage-Gated Sodium Channels Navl.5 in Human Breast Caner Cell Line MDA-MB-231

    Institute of Scientific and Technical Information of China (English)

    Rui GAO; Jing WANG; Yi SHEN; Ming LEI; Zehua WANG

    2009-01-01

    Voltage-gated sodium channels (VGSCs) are known to be involved in the initiation and progression of many malignancies,and the different subtypes of VGSCs play important roles in the metastasis cascade of many tumors.This study investigated the functional expression of Nav 1.5 and its effect on invasion behavior of human breast cancer cell line MDA-MB-231.The mRNA and pro-tein expression of Navl.5 was detected by real time PCR,Western Blot and immunofluorescence.The effects of Navl.5 on cell proliferation,migration and invasion were respectively assessed by MTT and Transwell.The effects of Nav1.5 on the secretion of matrix metalloproteases (MMPs) by MDA-MB-231 were analyzed by RT-PCR.The over-expressed Navl.5 was present on the membrane of MDA-MB-231 cells.The invasion ability in vitro and the MMP-9 mRNA expression were respec-tively decreased to (47.82±0.53)% and (43.97±0.64)% (P<0.05) respectively in MDA-MB-231 cells treated with VGSCs specific inhibitor tetrodotoxin (TTX) by blocking Navl.5 activity.It was con-eluded that Nav1.5 functional expression potentiated the invasive behavior of human breast cancer cell line MDA-MB-231 by increasing the secretion of MMP-9.

  3. Novel Mutations in the Voltage-Gated Sodium Channel of Pyrethroid-Resistant Varroa destructor Populations from the Southeastern USA

    Science.gov (United States)

    González-Cabrera, Joel; Rodríguez-Vargas, Sonia; Davies, T. G. Emyr; Field, Linda M.; Schmehl, Daniel; Ellis, James D.; Krieger, Klemens; Williamson, Martin S.

    2016-01-01

    The parasitic mite Varroa destructor has a significant worldwide impact on bee colony health. In the absence of control measures, parasitized colonies invariably collapse within 3 years. The synthetic pyrethroids tau-fluvalinate and flumethrin have proven very effective at managing this mite within apiaries, but intensive control programs based mainly on one active ingredient have led to many reports of pyrethroid resistance. In Europe, a modification of leucine to valine at position 925 (L925V) of the V. destructor voltage-gated sodium channel was correlated with resistance, the mutation being found at high frequency exclusively in hives with a recent history of pyrethroid treatment. Here, we identify two novel mutations, L925M and L925I, in tau-fluvalinate resistant V. destructor collected at seven sites across Florida and Georgia in the Southeastern region of the USA. Using a multiplexed TaqMan® allelic discrimination assay, these mutations were found to be present in 98% of the mites surviving tau-fluvalinate treatment. The mutations were also found in 45% of the non-treated mites, suggesting a high potential for resistance evolution if selection pressure is applied. The results from a more extensive monitoring programme, using the Taqman® assay described here, would clearly help beekeepers with their decision making as to when to include or exclude pyrethroid control products and thereby facilitate more effective mite management programmes. PMID:27191597

  4. Novel Mutations in the Voltage-Gated Sodium Channel of Pyrethroid-Resistant Varroa destructor Populations from the Southeastern USA.

    Directory of Open Access Journals (Sweden)

    Joel González-Cabrera

    Full Text Available The parasitic mite Varroa destructor has a significant worldwide impact on bee colony health. In the absence of control measures, parasitized colonies invariably collapse within 3 years. The synthetic pyrethroids tau-fluvalinate and flumethrin have proven very effective at managing this mite within apiaries, but intensive control programs based mainly on one active ingredient have led to many reports of pyrethroid resistance. In Europe, a modification of leucine to valine at position 925 (L925V of the V. destructor voltage-gated sodium channel was correlated with resistance, the mutation being found at high frequency exclusively in hives with a recent history of pyrethroid treatment. Here, we identify two novel mutations, L925M and L925I, in tau-fluvalinate resistant V. destructor collected at seven sites across Florida and Georgia in the Southeastern region of the USA. Using a multiplexed TaqMan® allelic discrimination assay, these mutations were found to be present in 98% of the mites surviving tau-fluvalinate treatment. The mutations were also found in 45% of the non-treated mites, suggesting a high potential for resistance evolution if selection pressure is applied. The results from a more extensive monitoring programme, using the Taqman® assay described here, would clearly help beekeepers with their decision making as to when to include or exclude pyrethroid control products and thereby facilitate more effective mite management programmes.

  5. First chemical synthesis of a scorpion alpha-toxin affecting sodium channels: the Aah I toxin of Androctonus australis hector.

    Science.gov (United States)

    M'Barek, Sarrah; Fajloun, Ziad; Cestèle, Sandrine; Devaux, Christiane; Mansuelle, Pascal; Mosbah, Amor; Jouirou, Besma; Mantegazza, Massimo; Van Rietschoten, Jurphaas; El Ayeb, Mohamed; Rochat, Hervé; Sabatier, Jean-Marc; Sampieri, François

    2004-11-01

    Aah I is a 63-residue alpha-toxin isolated from the venom of the Buthidae scorpion Androctonus australis hector, which is considered to be the most dangerous species. We report here the first chemical synthesis of Aah I by the solid-phase method, using a Fmoc strategy. The synthetic toxin I (sAah I) was renatured in DMSO-Tris buffer, purified and subjected to thorough analysis and comparison with the natural toxin. The sAah I showed physico-chemical (CD spectrum, molecular mass, HPLC elution), biochemical (amino-acid composition, sequence), immunochemical and pharmacological properties similar to those of the natural toxin. The synthetic toxin was recognized by a conformation-dependent monoclonal anti-Aah I antibody, with an IC50 value close to that for the natural toxin. Following intracerebroventricular injection, the synthetic and the natural toxins were similarly lethal to mice. In voltage-clamp experiments, Na(v) 1.2 sodium channel inactivation was inhibited by the application of sAah I or of the natural toxin in a similar way. This work describes a simple protocol for the chemical synthesis of a scorpion alpha-toxin, making it possible to produce structural analogues in time.

  6. Novel Mutations in the Voltage-Gated Sodium Channel of Pyrethroid-Resistant Varroa destructor Populations from the Southeastern USA.

    Science.gov (United States)

    González-Cabrera, Joel; Rodríguez-Vargas, Sonia; Davies, T G Emyr; Field, Linda M; Schmehl, Daniel; Ellis, James D; Krieger, Klemens; Williamson, Martin S

    2016-01-01

    The parasitic mite Varroa destructor has a significant worldwide impact on bee colony health. In the absence of control measures, parasitized colonies invariably collapse within 3 years. The synthetic pyrethroids tau-fluvalinate and flumethrin have proven very effective at managing this mite within apiaries, but intensive control programs based mainly on one active ingredient have led to many reports of pyrethroid resistance. In Europe, a modification of leucine to valine at position 925 (L925V) of the V. destructor voltage-gated sodium channel was correlated with resistance, the mutation being found at high frequency exclusively in hives with a recent history of pyrethroid treatment. Here, we identify two novel mutations, L925M and L925I, in tau-fluvalinate resistant V. destructor collected at seven sites across Florida and Georgia in the Southeastern region of the USA. Using a multiplexed TaqMan® allelic discrimination assay, these mutations were found to be present in 98% of the mites surviving tau-fluvalinate treatment. The mutations were also found in 45% of the non-treated mites, suggesting a high potential for resistance evolution if selection pressure is applied. The results from a more extensive monitoring programme, using the Taqman® assay described here, would clearly help beekeepers with their decision making as to when to include or exclude pyrethroid control products and thereby facilitate more effective mite management programmes. PMID:27191597

  7. Novel point mutations in the German cockroach para sodium channel gene are associated with knockdown resistance (kdr) to pyrethroid insecticides.

    Science.gov (United States)

    Liu, Z; Valles, S M; Dong, K

    2000-10-01

    Knockdown resistance (kdr) to pyrethroid insecticides has been attributed to point mutations in the para sodium channel gene in more than a half dozen insect pest species. In this study, we identified two novel para mutations in five highly resistant kdr-type German cockroach strains. The two mutations, from glutamic acid (E434) to lysine (K434) and from cysteine (C764) to arginine (R764), respectively, are located in the first intracellular linker connecting domains I and II. E434K is located near the beginning of the linker (closest to domain I), whereas C764R is found toward the end of the linker (closest to domain II). Two additional mutations from aspartic acid (D58) to glycine (G58), and from proline (P1880) to leucine (L1888), respectively, were found in one of the resistant strains. The four mutations coexist with the previously identified leucine to phenylalanine (L993F) kdr mutation in IIS6, and are present only in the highly resistant individuals of a given strain. These findings suggest that these mutations might be responsible for high levels of knockdown resistance toward pyrethroid insecticides in the German cockroach. PMID:10899465

  8. Astrocytes expressing mutant SOD1 and TDP43 trigger motoneuron death that is mediated via sodium channels and nitroxidative stress

    Directory of Open Access Journals (Sweden)

    Fabiola eRojas

    2014-02-01

    Full Text Available Amyotrophic lateral sclerosis (ALS is a fatal paralytic disorder caused by dysfunction and degeneration of motor neurons. Multiple disease-causing mutations, including in the genes for SOD1 and TDP-43, have been identified in ALS. Astrocytes expressing mutant SOD1 are strongly implicated in the pathogenesis of ALS: we have shown that media conditioned by astrocytes carrying mutant SOD1G93A contains toxic factor(s that kill motoneurons by activating voltage-sensitive sodium (Nav channels. In contrast, a recent study suggests that astrocytes expressing mutated TDP43 contribute to ALS pathology, but do so via cell-autonomous processes and lack non-cell-autonomous toxicity. Here we investigate whether astrocytes that express diverse ALS-causing mutations release toxic factor(s that induce motoneuron death, and if so, whether they do so via a common pathogenic pathway. We exposed primary cultures of wild-type spinal cord cells to conditioned medium derived from astrocytes (ACM that express SOD1 (ACM-SOD1G93A and ACM-SOD1G86R or TDP43 (ACM-TDP43A315T mutants; we show that such exposure rapidly (within 30-60 minutes increases dichlorofluorescein (DCF fluorescence (indicative of nitroxidative stress and leads to extensive motoneuron-specific death within a few days. Co-application of the diverse ACMs with anti-oxidants Trolox or esculetin (but not with resveratrol strongly improves motoneuron survival. We also find that co-incubation of the cultures in the ACMs with Nav channel blockers (including mexiletine, spermidine or riluzole prevents both intracellular nitroxidative stress and motoneuron death. Together, our data document that two completely unrelated ALS models lead to the death of motoneuron via non-cell-autonomous processes, and show that astrocytes expressing mutations in SOD1 and TDP43 trigger such cell death through a common pathogenic pathway that involves nitroxidative stress, induced at least in part by Nav channel activity.

  9. Three Peptide Modulators of the Human Voltage-Gated Sodium Channel 1.7, an Important Analgesic Target, from the Venom of an Australian Tarantula

    OpenAIRE

    Chun Yuen Chow; Ben Cristofori-Armstrong; Undheim, Eivind A.B.; Glenn F. King; Rash, Lachlan D

    2015-01-01

    Voltage-gated sodium (NaV) channels are responsible for propagating action potentials in excitable cells. NaV1.7 plays a crucial role in the human pain signalling pathway and it is an important therapeutic target for treatment of chronic pain. Numerous spider venom peptides have been shown to modulate the activity of NaV channels and these peptides represent a rich source of research tools and therapeutic lead molecules. The aim of this study was to determine the diversity of NaV1.7-active pe...

  10. AtHKT1;1 mediates nernstian sodium channel transport properties in Arabidopsis root stelar cells.

    Directory of Open Access Journals (Sweden)

    Shaowu Xue

    Full Text Available The Arabidopsis AtHKT1;1 protein was identified as a sodium (Na⁺ transporter by heterologous expression in Xenopus laevis oocytes and Saccharomyces cerevisiae. However, direct comparative in vivo electrophysiological analyses of a plant HKT transporter in wild-type and hkt loss-of-function mutants has not yet been reported and it has been recently argued that heterologous expression systems may alter properties of plant transporters, including HKT transporters. In this report, we analyze several key functions of AtHKT1;1-mediated ion currents in their native root stelar cells, including Na⁺ and K⁺ conductances, AtHKT1;1-mediated outward currents, and shifts in reversal potentials in the presence of defined intracellular and extracellular salt concentrations. Enhancer trap Arabidopsis plants with GFP-labeled root stelar cells were used to investigate AtHKT1;1-dependent ion transport properties using patch clamp electrophysiology in wild-type and athkt1;1 mutant plants. AtHKT1;1-dependent currents were carried by sodium ions and these currents were not observed in athkt1;1 mutant stelar cells. However, K⁺ currents in wild-type and athkt1;1 root stelar cell protoplasts were indistinguishable correlating with the Na⁺ over K⁺ selectivity of AtHKT1;1-mediated transport. Moreover, AtHKT1;1-mediated currents did not show a strong voltage dependence in vivo. Unexpectedly, removal of extracellular Na⁺ caused a reduction in AtHKT1;1-mediated outward currents in Columbia root stelar cells and Xenopus oocytes, indicating a role for external Na⁺ in regulation of AtHKT1;1 activity. Shifting the NaCl gradient in root stelar cells showed a Nernstian shift in the reversal potential providing biophysical evidence for the model that AtHKT1;1 mediates passive Na⁺ channel transport properties.

  11. Improving charge injection in high-mobility rubrene crystals: From contact-limited to channel-dominated transistors

    Science.gov (United States)

    Zimmerling, Tino; Batlogg, Bertram

    2014-04-01

    With progressively improving charge carrier mobility in organic semiconductors and miniaturization of organic field-effect transistors (OFETs), low contact resistances become ever more important. To study the capabilities of metal electrodes in OFETs and to explore the transition from contact-limited to channel-dominated transistor operation, we used flip-crystal FETs with gold electrodes having different contact resistances Rc to high-quality rubrene crystals. 4-terminal transfer and output measurements reveal that Rc decreases from 105-106 Ω cm for 15 min air exposure to 3 × 103 Ωcm for at least 5 h air exposure of the gold electrodes before the flip-crystal FET is assembled. We conclude the reduction of Rc to be caused by a growing contamination layer on the gold electrodes that weakens the electrostatic coupling between rubrene crystal and gold electrode, and lowers the Schottky contact diode parameter V0. In channel-dominated (low Rc) FETs, the mobility is in the range of 10-17 cm2/(Vs); in contrast, in contact-limited (high Rc) FETs, the apparent mobility decreases significantly with increasing contact resistance. The apparent μ - Rc dependence is not intrinsic, but rather the result of incorrect assumptions of the potential and the charge carrier density in the channel region. Thus, the development of high-mobility organic semiconductors requires further efforts to improve contacts beyond traditional metal electrodes.

  12. Determining the Advantages, Costs, and Trade-Offs of a Novel Sodium Channel Mutation in the Copepod Acartia hudsonica to Paralytic Shellfish Toxins (PST.

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    Michael Finiguerra

    Full Text Available The marine copepod Acartia hudsonica was shown to be adapted to dinoflagellate prey, Alexandrium fundyense, which produce paralytic shellfish toxins (PST. Adaptation to PSTs in other organisms is caused by a mutation in the sodium channel. Recently, a mutation in the sodium channel in A. hudsonica was found. In this study, we rigorously tested for advantages, costs, and trade-offs associated with the mutant isoform of A. hudsonica under toxic and non-toxic conditions. We combined fitness with wild-type: mutant isoform ratio measurements on the same individual copepod to test our hypotheses. All A. hudsonica copepods express both the wild-type and mutant sodium channel isoforms, but in different proportions; some individuals express predominantly mutant (PMI or wild-type isoforms (PWI, while most individuals express relatively equal amounts of each (EI. There was no consistent pattern of improved performance as a function of toxin dose for egg production rate (EPR, ingestion rate (I, and gross growth efficiency (GGE for individuals in the PMI group relative to individuals in the PWI expression group. Neither was there any evidence to indicate a fitness benefit to the mutant isoform at intermediate toxin doses. No clear advantage under toxic conditions was associated with the mutation. Using a mixed-diet approach, there was also no observed relationship between individual wild-type: mutant isoform ratios and among expression groups, on both toxic and non-toxic diets, for eggs produced over three days. Lastly, expression of the mutant isoform did not mitigate the negative effects of the toxin. That is, the reductions in EPR from a toxic to non-toxic diet for copepods were independent of expression groups. Overall, the results did not support our hypotheses; the mutant sodium channel isoform does not appear to be related to adaptation to PST in A. hudsonica. Other potential mechanisms responsible for the adaptation are discussed.

  13. A gain-of-function voltage-gated sodium channel 1.8 mutation drives intense hyperexcitability of A- and C-fiber neurons.

    Science.gov (United States)

    Garrison, Sheldon R; Weyer, Andy D; Barabas, Marie E; Beutler, Bruce A; Stucky, Cheryl L

    2014-05-01

    Therapeutic use of general sodium channel blockers, such as lidocaine, can substantially reduce the enhanced activity in sensory neurons that accompanies chronic pain after nerve or tissue injury. However, because these general blockers have significant side effects, there is great interest in developing inhibitors that specifically target subtypes of sodium channels. Moreover, some idiopathic small-fiber neuropathies are driven by gain-of-function mutations in specific sodium channel subtypes. In the current study, we focus on one subtype, the voltage-gated sodium channel 1.8 (Nav1.8). Nav1.8 is preferentially expressed in nociceptors, and gain-of-function mutations in Nav1.8 result in painful mechanical hypersensitivity in humans. Here, we used the recently developed gain-of-function Nav1.8 transgenic mouse strain, Possum, to investigate Nav1.8-mediated peripheral afferent hyperexcitability. This gain-of-function mutation resulted in markedly increased mechanically evoked action potential firing in subclasses of Aβ, Aδ, and C fibers. Moreover, mechanical stimuli initiated bursts of action potential firing in specific subpopulations that continued for minutes after removal of the force and were not susceptible to conduction failure. Surprisingly, despite the intense afferent firing, the behavioral effects of the Nav1.8 mutation were quite modest, as only frankly noxious stimuli elicited enhanced pain behavior. These data demonstrate that a Nav1.8 gain-of-function point mutation contributes to intense hyperexcitability along the afferent axon within distinct sensory neuron subtypes. PMID:24447515

  14. Effect of Gender on the Pharmacokinetics of Eslicarbazepine Acetate (BIA 2-093), a New Voltage-gated Sodium Channel Blocker

    OpenAIRE

    Falcão, Amílcar; Maia, Joana; Almeida, Luís; Mazur, Dago; Gellert, Manfred; Soares-da-Silva, Patrício

    2007-01-01

    Purpose. To determine the effect of gender on the pharmacokinetics of eslicarbazepine acetate, a novel voltage-gated sodium channel blocker in the development for the treatment of epilepsy and bipolar disorder. Methods. Single-centre, open-label, parallel-group study in 12 female and 12 male healthy subjects. The study consisted of a single-dose (600 mg) period and a multiple-dose (600 mg, oncedaily, for 8 days) period, separated by 4 days. Results. Eslicarbazepine acetate w...

  15. Evolutionary adaptation of the amino acid and codon usage of the mosquito sodium channel following insecticide selection in the field mosquitoes.

    Directory of Open Access Journals (Sweden)

    Qiang Xu

    Full Text Available Target site insensitivity resulting from point mutations within the voltage-gated sodium channel of the insect nervous system is known to be of primary importance in the development of resistance to pyrethroid insecticides. This study shifts current research paradigms by conducting, for the first time, a global analysis of all the naturally occurring mutations, both nonsynonymous and synonymous mutations, as well as mutation combinations in the entire mosquito sodium channel of Culex quinquefasciatus and analyzing their evolutionary and heritable feature and roles in insecticide resistance. Through a systematic analysis of comparing nucleotide polymorphisms in the entire sodium channel cDNAs of individuals between susceptible and resistant mosquito strains, between field parental mosquitoes and their permethrin selected offspring, and among different mosquito groups categorized by their levels of tolerance to specific permethrin concentrations within and among the mosquito strains of the field parental strains and their permethrin selected offspring, 3 nonsynonymous (A(109S, L(982F, and W(1573R and 6 synonymous (L(852, G(891, A(1241, D(1245, P(1249, and G(1733 mutations were identified. The co-existence of all 9 mutations, both nonsynonymous and synonymous, and their homozygousity were found to be important factors for high levels of resistance. Our study, for the first time, provide a strong case demonstrating the co-existence of both nonsynonymous and synonymous mutations in the sodium channel of resistant mosquitoes in response to insecticide resistance and the inheritance of these mutations in the offspring of field mosquito strains following insecticide selection.

  16. Tarantula Huwentoxin-IV Inhibits Neuronal Sodium Channels by Binding to Receptor Site 4 and Trapping the Domain II Voltage Sensor in the Closed Configuration*S⃞

    OpenAIRE

    Xiao, Yucheng; Bingham, Jon-Paul; Zhu, Weiguo; Moczydlowski, Edward; Liang, Songping; Cummins, Theodore R.

    2008-01-01

    Peptide toxins with high affinity, divergent pharmacological functions, and isoform-specific selectivity are powerful tools for investigating the structure-function relationships of voltage-gated sodium channels (VGSCs). Although a number of interesting inhibitors have been reported from tarantula venoms, little is known about the mechanism for their interaction with VGSCs. We show that huwentoxin-IV (HWTX-IV), a 35-residue peptide from tarantula Ornithoctonus huwena v...

  17. Molecular Surface of JZTX-V (β-Theraphotoxin-Cj2a Interacting with Voltage-Gated Sodium Channel Subtype NaV1.4

    Directory of Open Access Journals (Sweden)

    Ji Luo

    2014-07-01

    Full Text Available Voltage-gated sodium channels (VGSCs; NaV1.1–NaV1.9 have been proven to be critical in controlling the function of excitable cells, and human genetic evidence shows that aberrant function of these channels causes channelopathies, including epilepsy, arrhythmia, paralytic myotonia, and pain. The effects of peptide toxins, especially those isolated from spider venom, have shed light on the structure–function relationship of these channels. However, most of these toxins have not been analyzed in detail. In particular, the bioactive faces of these toxins have not been determined. Jingzhaotoxin (JZTX-V (also known as β-theraphotoxin-Cj2a is a 29-amino acid peptide toxin isolated from the venom of the spider Chilobrachys jingzhao. JZTX-V adopts an inhibitory cysteine knot (ICK motif and has an inhibitory effect on voltage-gated sodium and potassium channels. Previous experiments have shown that JZTX-V has an inhibitory effect on TTX-S and TTX-R sodium currents on rat DRG cells with IC50 values of 27.6 and 30.2 nM, respectively, and is able to shift the activation and inactivation curves to the depolarizing and the hyperpolarizing direction, respectively. Here, we show that JZTX-V has a much stronger inhibitory effect on NaV1.4, the isoform of voltage-gated sodium channels predominantly expressed in skeletal muscle cells, with an IC50 value of 5.12 nM, compared with IC50 values of 61.7–2700 nM for other heterologously expressed NaV1 subtypes. Furthermore, we investigated the bioactive surface of JZTX-V by alanine-scanning the effect of toxin on NaV1.4 and demonstrate that the bioactive face of JZTX-V is composed of three hydrophobic (W5, M6, and W7 and two cationic (R20 and K22 residues. Our results establish that, consistent with previous assumptions, JZTX-V is a Janus-faced toxin which may be a useful tool for the further investigation of the structure and function of sodium channels.

  18. Voltage-gated sodium channel as a target for metastatic risk reduction with re-purposed drugs [version 1; referees: 2 approved

    Directory of Open Access Journals (Sweden)

    Tomas Koltai

    2015-07-01

    Full Text Available Objective: To determine the exact role of sodium channel proteins in migration, invasion and metastasis and understand the possible anti-invasion and anti-metastatic activity of repurposed drugs with voltage gated sodium channel blocking properties. Material and methods: A review of the published medical literature was performed searching for pharmaceuticals used in daily practice, with inhibitory activity on voltage gated sodium channels. For every drug found, the literature was reviewed in order to define if it may act against cancer cells as an anti-invasion and anti-metastatic agent and if it was tested with this purpose in the experimental and clinical settings. Results: The following pharmaceuticals that fulfill the above mentioned effects, were found: phenytoin, carbamazepine, valproate, lamotrigine, ranolazine, resveratrol, ropivacaine, lidocaine, mexiletine, flunarizine, and riluzole. Each of them are independently described and analyzed. Conclusions: The above mentioned pharmaceuticals have shown anti-metastatic and anti-invasion activity and many of them deserve to be tested in well-planned clinical trials as adjunct therapies for solid tumors and as anti-metastatic agents. Antiepileptic drugs like phenytoin, carbamazepine and valproate and the vasodilator flunarizine emerged as particularly useful for anti-metastatic purposes.

  19. 昆虫钠离子通道抑制剂的应用研究进展%Research Progress of Sodium Ion Channel Inhibitors of Insects

    Institute of Scientific and Technical Information of China (English)

    苏旺苍; 吴仁海; 张永超; 张燕飞; 王恒亮

    2012-01-01

    电压敏感的钠离子通道是神经细胞兴奋传导的基础,也是神经毒性杀虫剂最主要的作用靶标.为此,综述了昆虫钠离子通道抑制剂滴滴涕及其类似物、拟除虫菊酯类、吡唑类、二苯基甲醇哌啶类、藜芦碱类、N-烷基酰胺类杀虫剂及其他生物毒素的应用研究进展,并对其开发前景进行了展望.%Sodium ion channel is one of the chief target sites of neurotoxic pesticides. This paper reviews the advance of main types of sodium ion channel inhibitors,!, e. DDT and analogues, pyre-throid,pyrazolines,benzhydrol-piperidines,veratrine,N-alkyl amides and other biotoxins. In addition, the prospects of sodium ion channel inhibitors are analyzed.

  20. Charge density dependent two-channel conduction in organic electric double layer transistors (EDLTs).

    Science.gov (United States)

    Xie, Wei; Liu, Feilong; Shi, Sha; Ruden, P Paul; Frisbie, C Daniel

    2014-04-23

    A transport model based on hole-density-dependent trapping is proposed to explain the two unusual conductivity peaks at surface hole densities above 10(13) cm(-2) in rubrene electric double layer transistors (EDLTs). Hole transport in rubrene is described to occur via multiple percolation pathways, where conduction is dominated by transport in the free-site channel at low hole density, and in the trap-site channel at larger hole density. PMID:24496822

  1. Epithelial sodium channel (ENaC) family: Phylogeny, structure-function, tissue distribution, and associated inherited diseases.

    Science.gov (United States)

    Hanukoglu, Israel; Hanukoglu, Aaron

    2016-04-01

    The epithelial sodium channel (ENaC) is composed of three homologous subunits and allows the flow of Na(+) ions across high resistance epithelia, maintaining body salt and water homeostasis. ENaC dependent reabsorption of Na(+) in the kidney tubules regulates extracellular fluid (ECF) volume and blood pressure by modulating osmolarity. In multi-ciliated cells, ENaC is located in cilia and plays an essential role in the regulation of epithelial surface liquid volume necessary for cilial transport of mucus and gametes in the respiratory and reproductive tracts respectively. The subunits that form ENaC (named as alpha, beta, gamma and delta, encoded by genes SCNN1A, SCNN1B, SCNN1G, and SCNN1D) are members of the ENaC/Degenerin superfamily. The earliest appearance of ENaC orthologs is in the genomes of the most ancient vertebrate taxon, Cyclostomata (jawless vertebrates) including lampreys, followed by earliest representatives of Gnathostomata (jawed vertebrates) including cartilaginous sharks. Among Euteleostomi (bony vertebrates), Actinopterygii (ray finned-fishes) branch has lost ENaC genes. Yet, most animals in the Sarcopterygii (lobe-finned fish) branch including Tetrapoda, amphibians and amniotes (lizards, crocodiles, birds, and mammals), have four ENaC paralogs. We compared the sequences of ENaC orthologs from 20 species and established criteria for the identification of ENaC orthologs and paralogs, and their distinction from other members of the ENaC/Degenerin superfamily, especially ASIC family. Differences between ENaCs and ASICs are summarized in view of their physiological functions and tissue distributions. Structural motifs that are conserved throughout vertebrate ENaCs are highlighted. We also present a comparative overview of the genotype-phenotype relationships in inherited diseases associated with ENaC mutations, including multisystem pseudohypoaldosteronism (PHA1B), Liddle syndrome, cystic fibrosis-like disease and essential hypertension. PMID

  2. Sodium channel-inhibiting drugs and cancer survival: protocol for a cohort study using the CPRD primary care database

    Science.gov (United States)

    Fairhurst, Caroline; Martin, Fabiola; Watt, Ian; Doran, Tim; Bland, Martin

    2016-01-01

    Introduction Voltage-gated sodium channel (VGSC)-inhibiting drugs are commonly used to treat epilepsy and cardiac arrhythmia. VGSCs are also widely expressed in various cancers, including those of the breast, bowel and prostate. A number of VGSC-inhibiting drugs have been shown to inhibit cancer cell proliferation, invasion, tumour growth and metastasis in preclinical models, suggesting that VGSCs may be novel molecular targets for cancer treatment. Surprisingly, we previously found that prior exposure to VGSC-inhibiting drugs may be associated with reduced overall survival in patients with cancer, but we were unable to control for the cause of death or indication for prescription. The purpose of the present study is to interrogate a different database to further investigate the relationship between VGSC-inhibiting drugs and cancer-specific survival. Methods and analysis A cohort study using primary care data from the Clinical Practice Research Datalink database will include patients with diagnosis of breast, bowel and prostate cancer (13 000). The primary outcome will be cancer-specific survival from the date of cancer diagnosis. Cox proportional hazards regression will be used to compare survival of patients taking VGSC-inhibiting drugs (including antiepileptic drugs and class I antiarrhythmic agents) with patients with cancer not taking these drugs, adjusting for cancer type, age and sex. Drug exposure will be treated as a time-varying covariate to account for potential immortal time bias. Various sensitivity and secondary analyses will be performed. Ethics and dissemination The project has been reviewed and approved by the University of York Ethical Review Process. Results will be presented at an international conference and published in open access peer-reviewed journals according to the STROBE and RECORD guidelines. PMID:27601493

  3. Regulation of epithelial sodium channel a-subunit expression by adenosine receptor A2a in alveolar epithelial cells

    Institute of Scientific and Technical Information of China (English)

    DENG Wang; WANG Dao-xin; ZHANG Wei; LI Chang-yi

    2011-01-01

    Background The amiloride-sensitive epithelial sodium channel a-subunit (a-ENaC) is an important factor for alveolar fluid clearance during acute lung injury. The relationship between adenosine receptor A2a (A2aAR) expressed in alveolar epithelial cells and aα-ENaC is poorly understood. We targeted the A2aAR in this study to investigate its role in the expression of αa-ENaC and in acute lung injury.Methods A549 cells were incubated with different concentrations of A2aAR agonist CGS-21680 and with 100 μmol/L CGS-21680 for various times. Rats were treated with lipopolysaccharide (LPS) after CGS-21680 was injected. Animals were sacrificed and tissue was harvested for evaluation of lung injury by analysis of the lung wet-to-dry weight ratio, lung permeability and myeloperoxidase activity. RT-PCR and Western blotting were used to determine the mRNA and protein expression levels of α-ENaC in A549 cells and alveolar type II epithelial cells.Results Both mRNA and protein levels of α-ENaC were markedly higher from 4 hours to 24 hours after exposure to 100μmol/L CGS-21680. There were significant changes from 0.1 umol/L to 100 μmol/L CGS-21680, with a positive correlation between increased concentrations of CGS-21680 and expression of α-ENaC. Treatment with CGS-21680during LPS induced lung injury protected the lung and promoted α-ENaC expression in the alveolar epithelial cells.Conclusion Activation of A2aAR has a protective effect during the lung injury, which may be beneficial to the prognosis of acute lung injury.

  4. A single blind randomized controlled clinical trial of mexiletine in amyotrophic lateral sclerosis: Efficacy and safety of sodium channel blocker phase II trial.

    Science.gov (United States)

    Shibuya, Kazumoto; Misawa, Sonoko; Kimura, Hideki; Noto, Yu-Ichi; Sato, Yasunori; Sekiguchi, Yukari; Iwai, Yuta; Mitsuma, Satsuki; Beppu, Minako; Watanabe, Keisuke; Fujimaki, Yumi; Tsuji, Yukiko; Shimizu, Toshio; Mizuno, Toshiki; Nakagawa, Masanori; Sawaguchi, Kyoko; Hanaoka, Hideki; Kuwabara, Satoshi

    2015-01-01

    Fasciculations are characteristic features of amyotrophic lateral sclerosis (ALS), and suggest motor nerve hyperexcitability. Recent reports have shown that an increase in persistent nodal sodium current is associated with shorter survival in ALS patients. This objective of this trial is to study the efficacy and safety of mexiletine, a sodium channel blocker, for ALS. Sixty eligible participants were randomly allocated (1:1) to riluzole 100 mg or riluzole plus mexiletine 300 mg. The primary endpoint was change in the revised ALS functional rating scale (ALSFRS-R) scores during six months. We also monitored strength-duration time constant (SDTC, a measure of persistent sodium current) in median motor axons. Results showed that during six months of treatment, changes in the ALSFRS-R score and SDTC were -7.0 ± 7.1 and -0.04 ± 0.1, respectively, in the riluzole group and -6.9 ± 6.4 and 0.04 ± 0.1, respectively, in the mexiletine group (p = 0.96 and 0.049). Adverse events amounted 20% in the riluzole and 33% in the mexiletine groups. In conclusion, the results suggest that daily 300 mg mexiletine has no effects on axonal sodium current and ALSFRS-R deterioration in ALS. We have to attempt another trial using a higher dose of mexiletine or other agents to suppress sodium currents and ALS progression in the future. PMID:25960085

  5. Investigation of positronium formation by molecular hydrogen ion impact with multiple scattering formulation in charge transfer channel

    Directory of Open Access Journals (Sweden)

    S Amiri

    2016-02-01

    Full Text Available In the present work the first and second order scattering amplitudes and the related phase were calculated in the charge transfer channel. The positronium formation, with the impact of molecular hydrogen ion, has been carried out using multiple channel scattering formulation and transition matrix. The calculation of differential cross section has been done by varying the scattering angle from 0 to 180 in the fixed orientation of the molecule. In the next calculation the scattering angles were fixed while the spatial molecular orientation was varied. At last the calculated differential cross section was compared with available results in the literature. The scattering angle spanned from 0 to 180 degrees in the second order nuclear and electronic terms were calculated while the molecular orientation was assumed to be fixed. Otherwise, the scattering angles were fixed in the calculation of the corresponding amplitudes while the orientation was varied. At last our calculations were compared with available results

  6. Observability of s-channel Heavy Charged Higgs at LHC Using Top Tagging Technique

    CERN Document Server

    Hashemi, Majid

    2015-01-01

    In this paper, the question of observability of a heavy charged Higgs in the mass range 400 GeV H+ -> tb at 14 TeV LHC. The analysis benefits from top tagging technique which is based on finding a fat jet as a result of the boosted top quark decay in signal events. A detailed hadron level analysis is performed and selection efficiencies are presented with different charged Higgs mass hypotheses. Finally running toy experiments and using pseudo-data, a fit over signal plus background distributions is performed to assess possibility of reconstructing the charged Higgs peak and its invariant mass measurement. It is shown that the charged Higgs mass can well be reconstructed in the mass range 500 GeV to 1 TeV, with a signal significance which depends on tanbeta. Eventually 5sigma discovery and 95% C.L. exclusion contours are also provided.

  7. Rectified motion in an asymmetrically structured channel due to induced-charge electrokinetic and thermo-kinetic phenomena

    Energy Technology Data Exchange (ETDEWEB)

    Sugioka, Hideyuki, E-mail: hsugioka@shinshu-u.ac.jp [Frontier Research Center, Canon Inc. 30-2, Shimomaruko 3-chome, Ohta-ku, Tokyo 146-8501, Japan and Department of Mechanical Systems Engineering, Shinshu University 4-17-1 Wakasato, Nagano 380-8553 (Japan)

    2016-02-15

    It would be advantageous to move fluid by the gradient of random thermal noises that are omnipresent in the natural world. To achieve this motion, we propose a rectifier that uses a thermal noise along with induced-charge electroosmosis and electrophoresis (ICEO and ICEP) around a metal post cylinder in an asymmetrically structured channel and numerically examine its rectification performance. By the boundary element method combined with the thin double layer approximation, we find that rectified motion occurs in the asymmetrically structured channel due to ICEO and ICEP. Further, by thermodynamical and equivalent circuit methods, we discuss a thermal voltage that drives a rectifier consisting of a fluidic channel of an electrolyte and an impedance as a noise source. Our calculations show that fluid can be moved in the asymmetrically structured channel by the fluctuation of electric fields due to a thermal noise only when there is a temperature difference. In addition, our simple noise argument provides a different perspective for the thermo-kinetic phenomena (around a metal post) which was predicted based on the electrolyte Seebeck effect in our previous paper [H. Sugioka, “Nonlinear thermokinetic phenomena due to the Seebeck effect,” Langmuir 30, 8621 (2014)].

  8. Charge exchange and energy loss of slowed down heavy ions channeled in silicon crystals; Echanges de charge et perte d'energie d'ions lourds ralentis, canalises dans des cristaux de silicium

    Energy Technology Data Exchange (ETDEWEB)

    Testa, E

    2005-10-15

    This work is devoted to the study of charge exchange processes and of the energy loss of highly charged heavy ions channeled in thin silicon crystals. The two first chapters present the techniques of heavy ion channeling in a crystal, the ion-electron processes and the principle of our simulations (charge exchange and trajectory of channeled ions). The next chapters describe the two experiments performed at the GSI facility in Darmstadt, the main results of which follow: the probability per target atom of the mechanical capture (MEC) of 20 MeV/u U{sup 91+} ions as a function of the impact parameter (with the help of our simulations), the observation of the strong polarization of the target electron gas by the study of the radiative capture and the slowing down of Pb{sup 81+} ions from 13 to 8,5 MeV/u in channeling conditions for which electron capture is strongly reduced. (author)

  9. Assessment of sodium channel mutations in Makah Tribal members of the U.S. Pacific Northwest as a potential mechanism of resistance to paralytic shellfish poisoning

    Science.gov (United States)

    Adams, Nicolaus G.; Robertson, Alison; Grattan, Lynn M.; Pendleton, Steve; Roberts, Sparkle; Tracy, J. Kathleen; Trainer, Vera L.

    2015-01-01

    The Makah Tribe of Neah Bay, Washington, has historically relied on the subsistence harvest of coastal seafood, including shellfish, which remains an important cultural and ceremonial resource. Tribal legend describes visitors from other tribes that died from eating shellfish collected on Makah lands. These deaths were believed to be caused by paralytic shellfish poisoning, a human illness caused by ingestion of shellfish contaminated with saxitoxins, which are produced by toxin-producing marine dinoflagellates on which the shellfish feed. These paralytic shellfish toxins include saxitoxin, a potent Na+ channel antagonist that binds to the pore region of voltage gated Na+ channels. Amino acid mutations in the Na+ channel pore have been demonstrated to confer resistance to saxitoxin in softshell clam populations exposed to paralytic shellfish toxins present in their environment. Because of the notion of resistance to paralytic shellfish toxins, we aimed to determine if a resistance strategy was possible in humans with historical exposure to toxins in shellfish. We collected, extracted and purified DNA from buccal swabs of 83 volunteer Makah tribal members and sequenced the skeletal muscle Na+ channel (Nav1.4) at nine loci to characterize potential mutations in the relevant saxitoxin binding regions. No mutations of these specific regions were identified after comparison to a reference sequence. This study suggests that any resistance of Makah Tribal members to saxitoxin is not a function of Nav1.4 modification but may be due to mutations in neuronal or cardiac sodium channels or some other mechanism unrelated to sodium channel function. PMID:27616973

  10. Charge states distribution of 3350 keV He ions channeled in silicon

    CERN Document Server

    Bentini, G G; Bianconi, M; Lotti, R; Lulli, G

    2002-01-01

    When an ion beam is aligned along a major crystalline axis the dominant interaction is with valence electrons. In this condition the charge exchange processes mostly concern the interaction between the incident ion and a quasi-free electron gas and a strong reduction of the charge-changing probabilities is expected. In this work, 3350 keV He sup + and He sup 2 sup + ions were aligned at small tilt angles about the axis of a 4650 A silicon crystalline membrane. The charge state distribution (CSD) of the transmitted ions was detected by an electro-magnetic analyzer having a very small acceptance angle. In these conditions the equilibration of the CSD was not yet reached and this allowed, making use of simple approximations, for the measurement of the valence electron loss cross-section.

  11. Elevated neuronal excitability due to modulation of the voltage-gated sodium channel Nav1.6 by Aβ1-42

    Directory of Open Access Journals (Sweden)

    Xi eWang

    2016-03-01

    Full Text Available Aberrant increases in neuronal network excitability may contribute to the cognitive deficits in Alzheimer’s disease (AD. However, the mechanisms underlying hyperexcitability are not fully understood. Such overexcitation of neuronal networks has been detected in the brains of APP/PS1 mice. In the present study, using current-clamp recording techniques, we observed that 12 days in vitro (DIV primary cultured pyramidal neurons from P0 APP/PS1 mice exhibited a more prominent action potential burst and a lower threshold than WT littermates. Moreover, after treatment with Aβ1-42 peptide, 12 DIV primary cultured neurons showed similar changes, to a greater degree than in controls. Voltage-clamp recordings revealed that the voltage-dependent sodium current density of neurons incubated with Aβ1-42 was significantly increased, without change in the voltage-dependent sodium channel kinetic characteristics. Immunohistochemistry and western blot results showed that, after treatment with Aβ1-42, expressions of Nav and Nav1.6 subtype increased in cultured neurons or APP/PS1 brains compared to control groups. The intrinsic neuronal hyperexcitability of APP/PS1 mice might thus be due to an increased expression of voltage-dependent sodium channels induced by Aβ1-42. These results may illuminate the mechanism of aberrant neuronal networks in AD.

  12. Effects of the β1 auxiliary subunit on modification of Rat Na(v)1.6 sodium channels expressed in HEK293 cells by the pyrethroid insecticides tefluthrin and deltamethrin.

    Science.gov (United States)

    He, Bingjun; Soderlund, David M

    2016-01-15

    We expressed rat Nav1.6 sodium channels with or without the rat β1 subunit in human embryonic kidney (HEK293) cells and evaluated the effects of the pyrethroid insecticides tefluthrin and deltamethrin on whole-cell sodium currents. In assays with the Nav1.6 α subunit alone, both pyrethroids prolonged channel inactivation and deactivation and shifted the voltage dependence of channel activation and steady-state inactivation toward hyperpolarization. Maximal shifts in activation were ~18 mV for tefluthrin and ~24 mV for deltamethrin. These compounds also caused hyperpolarizing shifts of ~10-14 mV in the voltage dependence of steady-state inactivation and increased in the fraction of sodium current that was resistant to inactivation. The effects of pyrethroids on the voltage-dependent gating greatly increased the size of sodium window currents compared to unmodified channels; modified channels exhibited increased probability of spontaneous opening at membrane potentials more negative than the normal threshold for channel activation and incomplete channel inactivation. Coexpression of Nav1.6 with the β1 subunit had no effect on the kinetic behavior of pyrethroid-modified channels but had divergent effects on the voltage-dependent gating of tefluthrin- or deltamethrin-modified channels, increasing the size of tefluthrin-induced window currents but decreasing the size of corresponding deltamethrin-induced currents. Unexpectedly, the β1 subunit did not confer sensitivity to use-dependent channel modification by either tefluthrin or deltamethrin. We conclude from these results that functional reconstitution of channels in vitro requires careful attention to the subunit composition of channel complexes to ensure that channels in vitro are faithful functional and pharmacological models of channels in neurons.

  13. Effects of the β1 auxiliary subunit on modification of Rat Na(v)1.6 sodium channels expressed in HEK293 cells by the pyrethroid insecticides tefluthrin and deltamethrin.

    Science.gov (United States)

    He, Bingjun; Soderlund, David M

    2016-01-15

    We expressed rat Nav1.6 sodium channels with or without the rat β1 subunit in human embryonic kidney (HEK293) cells and evaluated the effects of the pyrethroid insecticides tefluthrin and deltamethrin on whole-cell sodium currents. In assays with the Nav1.6 α subunit alone, both pyrethroids prolonged channel inactivation and deactivation and shifted the voltage dependence of channel activation and steady-state inactivation toward hyperpolarization. Maximal shifts in activation were ~18 mV for tefluthrin and ~24 mV for deltamethrin. These compounds also caused hyperpolarizing shifts of ~10-14 mV in the voltage dependence of steady-state inactivation and increased in the fraction of sodium current that was resistant to inactivation. The effects of pyrethroids on the voltage-dependent gating greatly increased the size of sodium window currents compared to unmodified channels; modified channels exhibited increased probability of spontaneous opening at membrane potentials more negative than the normal threshold for channel activation and incomplete channel inactivation. Coexpression of Nav1.6 with the β1 subunit had no effect on the kinetic behavior of pyrethroid-modified channels but had divergent effects on the voltage-dependent gating of tefluthrin- or deltamethrin-modified channels, increasing the size of tefluthrin-induced window currents but decreasing the size of corresponding deltamethrin-induced currents. Unexpectedly, the β1 subunit did not confer sensitivity to use-dependent channel modification by either tefluthrin or deltamethrin. We conclude from these results that functional reconstitution of channels in vitro requires careful attention to the subunit composition of channel complexes to ensure that channels in vitro are faithful functional and pharmacological models of channels in neurons. PMID:26708501

  14. Three-dimensional structure of the ion-channel forming peptide trichorzianin TA VII bound to sodium dodecyl sulfate micelles.

    Science.gov (United States)

    Condamine, E; Rebuffat, S; Prigent, Y; Ségalas, I; Bodo, B; Davoust, D

    1998-08-01

    Trichorzianin TA VII, Ac0 U1 A2 A3 U4 J5 Q6 U7 U8 U9 S10 L11 U12 P13 V14 U15 I16 Q17 Q18 Fol19, is a nonadecapeptide member of the peptaibol antibiotics biosynthesized by Trichoderma soil fungi, which is characterized by a high proportion of the alpha, alpha-dialkylated amino acids, alpha-aminoisobutyric acid (Aib, U) and isovaline (Iva, J), an acetylated N-terminus and a C-terminal phenylalaninol (Pheol, Fol). The main interest in such peptides stems from their ability to interact with phospholipid bilayers and form voltage-dependent transmembrane channels in planar lipid bilayers. In order to provide insights into the lipid-peptide interaction promoting the voltage gating, the conformational study of TA VII in the presence of perdeuterated sodium dodecyl sulfate (SDS-d25) micelles has been carried out. 1H sequential assignment have been performed with the use of two-dimensional homo- and -heteronuclear nmr techniques including double quantum filtered correlated spectroscopy, homonuclear Hartmann-Hahn, nuclear Overhauser effect spectroscopy, 1H-13C heteronuclear single quantum correlation, and heteronuclear multiple bond correlation. Conformational parameters, such as 3JNHC alpha H coupling constants, temperature coefficients of amide protons (delta gamma/delta TNH) and quantitative nuclear Overhauser enhancement data, lead to detailed structural information. Ninety-eight three-dimensional structures consistent with the nmr data were generated from 231 interproton distances six phi dihedral angle restraints, using restrained molecular dynamics and energy minimization calculations. The average rms deviation between the 98 refined structures and the energy-minimized average structure is 0.59 A for the backbone atoms. The structure of trichorzianin TA VII associated with SDS micelles, as determined by these methods, is characterized by two right-handed helical segments involving residues 1-8 and 11-19, linked by a beta-turn that leads to an angle about 90 degrees-100

  15. Natural mutations change the affinity of μ-theraphotoxin-Hhn2a to voltage-gated sodium channels.

    Science.gov (United States)

    Zhang, Fan; Liu, Yu; Zhang, Changxin; Li, Jing; Yang, Zuqin; Gong, Xue; Gan, Yunxiang; Chen, Ping; Liu, Zhonghua; Liang, Songping

    2015-01-01

    μ-Theraphotoxin-Hhn2a (HNTX-III) isolated from the venom of the spider Ornithoctonus hainana is a selective antagonist of neuronal tetrodotoxin-sensitive (TTX-S) voltage-gated sodium channels (VGSCs). Intriguingly, previous transcriptomic study revealed HNTX-III family consists of more than 15 precursors, in which the 20(th) and 24(th) residues of the mature sequences are variable. Try20 and Ser24 of HNTX-III are mutated to His20 and Asn24 of other members, respectively. In addition, the alkaline residue His26 of the potent VGSC inhibitor HNTX-III is substituted by acidic residue Asp of the weak VGSC inhibitor HNTX-I. Therefore, four mutants of HNTX-III, HNTX-III-Y20H, -S24N, -H26D and -Y20H/24N, were synthesized to examine the effects of these natural mutations on the inhibitory activity of HNTX-III. They were subjected to an electrophysiological screening on five VGSC subtypes (Nav1.3-1.5, Nav1.7 and Nav1.8) expressed on HEK293 cells by whole-cell patch clamp. Like HNTX-III, all mutants only displayed inhibitory activity on Nav1.3 and Nav1.7 among the five subtypes, but the inhibitory potency was much lower than that of HNTX-III. Regarding Nav1.7, the IC50 values of HNTX-III-Y20H, -S24N, -H26D and -Y20H/S24N were increased by approximately 62-, 8.4-, 49- and 19.5-folds compared with that of HNTX-III, respectively. Similar data were obtained for Nav1.3. Our results provide new insights into the activity-related residues of HNTX-III at genic level. Furthermore, the reduced potency of the four mutants probably reflects natural selection might favor and reserve the most potent bioactivity of HNTX-III which is one of the most abundant fractions of the venom. PMID:25447770

  16. Limited selection of sodium channel blocking toxin-producing bacteria from paralytic shellfish toxin-contaminated mussels (Aulacomya ater).

    Science.gov (United States)

    Vásquez, Mónica; Grüttner, Carol; Möeller, Blanca; Moore, Edward R B

    2002-01-01

    Paralytic shellfish toxins (PSTs) are sodium channel blocking (SCB) toxins, produced by cyanobacteria, as well as by marine dinoflagellates and their associated bacteria, and cause serious health and economic concern worldwide. In a previous study, approximately 70% of the bacteria enriched from PST-contaminated shellfish tissue and isolated on marine agar medium were observed to produce SCB toxins. In the study reported here, the high percentage of cultivable toxigenic bacteria is demonstrated to be obtained through a marked selection on marine agar medium. The cultivable as well as the total bacterial diversity associated with PST-contaminated shellfish collected from the Magallanes region in the south of Chile has been analysed. Approximately 80% of bacterial isolates, analysed by restriction analysis of PCR amplified ribosomal DNA (i.e., ARDRA fingerprinting), were limited to only two genotypic OTUs (operational taxonomic unit). Sequence determination and analysis of the 16S rDNA from representative isolates of both OTUs established them to be closely related to species of the Psychrobacter genus of the gamma-subclass of the Proteobacteria. The total bacterial diversity in the shellfish was further analysed, using a cultivation-independent strategy of extraction of total DNA from contaminated tissue, PCR-amplification of bacterial 16S rRNA genes, cloning of the PCR products and analysis of the cloned 16S rDNA sequence types by fingerprinting and sequencing. Only 2% of the cloned sequence types corresponded to species of the Psychrobacter genus. The 16S rDNA sequence types detected clustered with species of the y-Proteobacteria subclass, the Cytophaga-Flexibacter-Bacteroides (CFB), the Fusobacteria and the Firmicutes phyla. The level of diversity observed within the libraries of cloned 16S rDNA was markedly greater than that observed among isolates obtained through marine agar enrichment cultures from the same shellfish tissue. Additionally the predominant

  17. Effects of sodium metabisulfite on the expression of BK(Ca), K(ATP), and L-Ca(2+) channels in rat aortas in vivo and in vitro.

    Science.gov (United States)

    Zhang, Quanxi; Bai, Yunlong; Tian, Jingjing; Lei, Xiaodong; Li, Mei; Yang, Zhenhua; Meng, Ziqiang

    2015-03-01

    Sodium metabisulfite (SMB) is most commonly used as the preservative in many food preparations and drugs. So far, few studies about its negative effects were reported. The purpose of this study was to investigate the effect of SMB on the expression of big-conductance Ca(2+)-activated K(+) (BKCa), ATP-sensitive K(+) (KATP), and L-type calcium (L-Ca(2+)) channels in rat aorta in vivo and in vitro. The results showed that the mRNA and protein levels of the BKCa channel subunits α and β1 of aorta in rats were increased by SMB in vivo and in vitro. Similarly, the expression of the KATP channel subunits Kir6.1, Kir6.2, and SUR2B were increased by SMB. However, SMB at the highest concentration significantly decreased the expression of the L-Ca(2+) channel subunits Cav1.2 and Cav1.3. These results suggest that SMB can activate BKCa and KATP channels by increasing the expression of α, β1, and Kir6.1, Kir6.2, SUR2B respectively, while also inhibit L-Ca(2+) channels by decreasing the expression of Cav1.2 and Cav1.3 of aorta in rats. The molecular mechanism of SMB-induced vasorelaxant effect might be related to the expression changes of BKCa, KATP, and L-Ca(2+) channels subunits. Further work is needed to determine the relative contribution of each channel in SMB-mediated vasorelaxant effect.

  18. The Alternatively Spliced Form “b” of the Epithelial Sodium Channel α Subunit (α ENaC: Any Prior Evidence of its Existence?

    Directory of Open Access Journals (Sweden)

    Marlene F. Shehata

    2010-08-01

    Full Text Available The epithelial sodium channel (ENaC is critical in maintaining sodium balance across aldosterone-responsive epithelia. ENaC is a combined channel formed of three subunits (αβγ with α ENaC subunit being the most critical for channel functionality. In a previous report, we have demonstrated the existence and mRNA expression levels of four alternatively spliced forms of the α ENaC subunit denoted by -a, -b, -c and -d in kidney cortex of Dahl S and R rats. Of the four alternatively spliced forms presently identified, α ENaC-b is considered the most interesting for the following reasons: Aside from being a salt-sensitive transcript, α ENaC-b mRNA expression is ∼32 fold higher than α ENaC wildtype in kidney cortex of Dahl rats. Additionally, the splice site used to generate α ENaC-b is conserved across species. Finally, α ENaC-b mRNA expression is significantly higher in salt-resistant Dahl R rats versus salt-sensitive Dahl S rats. As such, this commentary aims to highlight some of the previously published research articles that described the existence of an additional protein band on α ENaC western blots that could account for α ENaC-b in other rat species.

  19. Experimental evidence of independence of nuclear de-channeling length on the particle charge sign

    CERN Document Server

    Bagli, E; Mazzolari, A; Bandiera, L; Germogli, G; Sytov, A I; De Salvador, D; Berra, A; Prest, M; Vallazza, E

    2016-01-01

    Under coherent interactions, particles undergo correlated collisions with the crystal lattice and their motion result in confinement in the fields of atomic planes, i.e. particle channeling. Other than coherently interacting with the lattice, particles also suffer incoherent interactions with individual nuclei and may leave their bounded motion, i.e., they de-channel. This latter is the main limiting factor for applications of coherent interactions in crystal-assisted particle steering. We experimentally investigated the nature of dechanneling of 120 GeV/c $e^{-}$ and $e^{+}$ in a bent silicon crystal at H4-SPS external line at CERN. We found out that while channeling efficiency differs significantly for $e^{-}$ ($4\\pm2$ $\\%$) and $e^{+}$ ($53\\pm2$ $\\%$), their nuclear dechanneling length is comparable, $(0.7\\pm0.1)$ mm for $e^{-}$ and $(0.85\\pm0.15)$ mm for $e^{+}$. The experimental proof of the equality of the nuclear dechanneling length for positrons and electrons is interpreted in terms of similar dynamic...

  20. Microspheric Na2Ti3O7 consisting of tiny nanotubes: an anode material for sodium-ion batteries with ultrafast charge-discharge rates

    Science.gov (United States)

    Wang, Wei; Yu, Chengjun; Lin, Zheshuai; Hou, Jungang; Zhu, Hongmin; Jiao, Shuqiang

    2012-12-01

    Conventionally, rechargeable batteries with a fast charge-discharge rate, while being able to be implemented in large-scale applications with low prices, are critical for new energy storage systems. In this work, first-principles simulations were employed to theoretically investigate the insertion of sodium into the Na2Ti3O7 structure. The result discovered that the theoretical capacity of Na2Ti3O7 was 311 mA h g-1. Furthermore, a microspheric Na2Ti3O7 material consisting of tiny nanotubes of ca. 8 nm in outside diameter and a few hundred nanometers in length has been synthesized. The galvanostatic charge-discharge measurements, using the as-prepared Na2Ti3O7 nanotubes as a working electrode with a voltage range of 0.01-2.5 V vs. Na+/Na, disclosed that a high capacity was maintained even under an ultrafast charge-discharge rate. At a current density of 354 mA g-1, the discharge capacity was maintained at 108 mA h g-1 over 100 cycles. Even at a very large current density of 3540 mA g-1, the discharge capacity was still 85 mA h g-1. HRTEM analysis and electrochemical tests proved that sodium ions could not only intercalate into the Na2Ti3O7 crystal, but could also be stored in the intracavity of the nanotubes. All of the results disclose that the as-prepared Na2Ti3O7 nanotubes are able to be used as anode materials in large-scale applications for rechargeable sodium-ion batteries at low cost while maintaining excellent performance.

  1. Effect of mitochondrial potassium channel on the renal protection mediated by sodium thiosulfate against ethylene glycol induced nephrolithiasis in rat model

    Directory of Open Access Journals (Sweden)

    N. Baldev

    2015-12-01

    Full Text Available Purpose: Sodium thiosulfate (STS is clinically reported to be a promising drug in preventing nephrolithiasis. However, its mechanism of action remains unclear. In the present study, we investigated the role of mitochondrial KATP channel in the renal protection mediated by STS. Materials and Methods: Nephrolithiasis was induced in Wistar rats by administrating 0.4% ethylene glycol (EG along with 1% ammonium chloride for one week in drinking water followed by only 0.75% EG for two weeks. Treatment groups received STS, mitochondrial KATP channel opener and closer exclusively or in combination with STS for two weeks. Results: Animals treated with STS showed normal renal tissue architecture, supported by near normal serum creatinine, urea and ALP activity. Diazoxide (mitochondria KATP channel opening treatment to the animal also showed normal renal tissue histology and improved serum chemistry. However, an opposite result was shown by glibenclamide (mitochondria KATP channel closer treated rats. STS administered along with diazoxide negated the renal protection rendered by diazoxide alone, while it imparted protection to the glibenclamide treated rats, formulating a mitochondria modulated STS action. Conclusion: The present study confirmed that STS render renal protection not only through chelation and antioxidant effect but also by modulating the mitochondrial KATP channel for preventing urolithiasis.

  2. Hypermorphic mutation of the voltage-gated sodium channel encoding gene Scn10a causes a dramatic stimulus-dependent neurobehavioral phenotype

    OpenAIRE

    Blasius, Amanda L.; Dubin, Adrienne E.; Petrus, Matt J.; Lim, Byung-Kwan; Narezkina, Anna; Criado, José R.; Wills, Derek N.; Xia, Yu; Moresco, Eva Marie Y.; Ehlers, Cindy; Knowlton, Kirk U.; Patapoutian, Ardem; Beutler, Bruce

    2011-01-01

    The voltage-gated sodium channel Nav1.8 is known to function in the transmission of pain signals induced by cold, heat, and mechanical stimuli. Sequence variants of human Nav1.8 have been linked to altered cardiac conduction. We identified an allele of Scn10a encoding the α-subunit of Nav1.8 among mice homozygous for N-ethyl-N-nitrosourea-induced mutations. The allele creates a dominant neurobehavioral phenotype termed Possum, characterized by transient whole-body tonic immobility induced by ...

  3. Synthesis and toxicopharmacological evaluation of m-hydroxymexiletine, the first metabolite of mexiletine more potent than the parent compound on voltage-gated sodium channels.

    Science.gov (United States)

    Catalano, Alessia; Desaphy, Jean-François; Lentini, Giovanni; Carocci, Alessia; Di Mola, Antonia; Bruno, Claudio; Carbonara, Roberta; De Palma, Annalisa; Budriesi, Roberta; Ghelardini, Carla; Perrone, Maria Grazia; Colabufo, Nicola Antonio; Conte Camerino, Diana; Franchini, Carlo

    2012-02-01

    The first synthesis of m-hydroxymexiletine (MHM) has been accomplished. MHM displayed hNav1.5 sodium channel blocking activity, and tests indicate it to be ∼2-fold more potent than the parent mexiletine and to have more favorable toxicological properties than mexiletine. Thus, MHM and possible related prodrugs might be studied as agents for the treatment of arrhythmias, neuropathic pain, and myotonias in substitution of mexiletine (metabolite switch), which has turned out to be tainted with common toxicity. PMID:22191686

  4. Measurement of light charged particles in the decay channels of medium-mass excited compound nuclei

    Directory of Open Access Journals (Sweden)

    Valdré S.

    2014-03-01

    Indeed, in this mass region (A ~ 100 models predict that shape transitions can occur at high spin values and relatively scarce data exist in the literature about coincidence measurements between evaporation residues and light charged particles. Signals of shape transitions can be found in the variations of the lineshape of high energy gamma rays emitted from the de-excitation of GDR states gated on different region of angular momenta. For this purpose it is important to keep under control the FE and FF processes, to regulate the statistical model parameters and to control the onset of possible pre-equilibrium emissions from 300 to 600 MeV bombarding energy.

  5. Voltage-gated sodium channel expression and action potential generation in differentiated NG108-15 cells

    OpenAIRE

    Liu Jinxu; Tu Huiyin; Zhang Dongze; Zheng Hong; Li Yu-Long

    2012-01-01

    Abstract Background The generation of action potential is required for stimulus-evoked neurotransmitter release in most neurons. Although various voltage-gated ion channels are involved in action potential production, the initiation of the action potential is mainly mediated by voltage-gated Na+ channels. In the present study, differentiation-induced changes of mRNA and protein expression of Na+ channels, Na+ currents, and cell membrane excitability were investigated in NG108-15 cells. Result...

  6. Exploring a heavy charged Higgs using jet substructure in a fully hadronic channel

    CERN Document Server

    Patrick, Riley; Williams, Anthony G

    2016-01-01

    In the framework of the type-II Two Higgs Doublet Model (2HDM-II) a charged Higgs search strategy is presented for the dominant production mode $gb \\rightarrow tH^\\pm$ at the 14 TeV LHC. We consider the decay process which includes $t \\rightarrow bW^\\pm$ and $H^\\pm \\rightarrow AW^\\pm$, and a fully hadronic final state consisting of $bb\\bar{b}+\\mbox{jets}+X$. Dictated by the $b \\rightarrow s\\gamma$ constraints which render $M_{H^\\pm} > 480$ GeV we study two scenarios in which the charged Higgs mass is 750 GeV and the pseudoscalar Higgs mass is 200 GeV and 500 GeV. In this mass scheme highly boosted final state objects are expected and handled with jet substructure techniques which also acts to suppress the standard model background. A detailed detector analysis is performed, followed by a multivariate analysis involving many kinematic variables to optimize signal to background significance. Finally the LHC search sensitivities for the two scenarios are presented for various integrated luminosities.

  7. A search for charge 1/3 third generation leptoquarks in muon channels

    Energy Technology Data Exchange (ETDEWEB)

    Uzunyan, Sergey A. [Northern Illinois Univ., DeKalb, IL (United States)

    2006-08-01

    Leptoquarks are exotic particles that have color, electric charge, and lepton number and appear in extended gauge theories and composite models. Current theory suggests that leptoquarks would come in three different generations corresponding to the three quark and lepton generations. We are searching for charge 1/3 third generation leptoquarks produced in p$\\bar{p}$ collisions at √s = 1.96 TeV using data collected by the D0 detector. Such leptoquarks would decay into either a tau-neutrino plus a b-quark or, if heavy enough, to a tau-lepton plus a t-quark. We present preliminary results on an analysis where both leptoquarks decay into neutrinos giving a final state with missing energy and two b-quarks using 367 pb-1 of Run II D0 data taken between August 2002 and September 2004. We place upper limits on σ(p$\\bar{p}$ → LQ$\\bar{LQ}$)B2 as a function of the leptoquark mass MLQ. Assuming B = 1, we exclude at the 95% confidence level third generation leptoquarks with MLQ < 197 GeV/c2.

  8. The Polarized Effect of Intracellular Calcium on the Renal Epithelial Sodium Channel Occurs as a Result of Subcellular Calcium Signaling Domains Maintained by Mitochondria.

    Science.gov (United States)

    Thai, Tiffany L; Yu, Ling; Galarza-Paez, Laura; Wu, Ming Ming; Lam, Ho Yin Colin; Bao, Hui Fang; Duke, Billie Jeanne; Al-Khalili, Otor; Ma, He-Ping; Liu, Bingchen; Eaton, Douglas C

    2015-11-27

    The renal epithelial sodium channel (ENaC) provides regulated sodium transport in the distal nephron. The effects of intracellular calcium ([Ca(2+)]i) on this channel are only beginning to be elucidated. It appears from previous studies that the [Ca(2+)]i increases downstream of ATP administration may have a polarized effect on ENaC, where apical application of ATP and the subsequent [Ca(2+)]i increase have an inhibitory effect on the channel, whereas basolateral ATP and [Ca(2+)]i have a stimulatory effect. We asked whether this polarized effect of ATP is, in fact, reflective of a polarized effect of increased [Ca(2+)]i on ENaC and what underlying mechanism is responsible. We began by performing patch clamp experiments in which ENaC activity was measured during apical or basolateral application of ionomycin to increase [Ca(2+)]i near the apical or basolateral membrane, respectively. We found that ENaC does indeed respond to increased [Ca(2+)]i in a polarized fashion, with apical increases being inhibitory and basolateral increases stimulating channel activity. In other epithelial cell types, mitochondria sequester [Ca(2+)]i, creating [Ca(2+)]i signaling microdomains within the cell that are dependent on mitochondrial localization. We found that mitochondria localize in bands just beneath the apical and basolateral membranes in two different cortical collecting duct principal cell lines and in cortical collecting duct principal cells in mouse kidney tissue. We found that inhibiting mitochondrial [Ca(2+)]i uptake destroyed the polarized response of ENaC to [Ca(2+)]i. Overall, our data suggest that ENaC is regulated by [Ca(2+)]i in a polarized fashion and that this polarization is maintained by mitochondrial [Ca(2+)]i sequestration. PMID:26451045

  9. Slack sodium-activated potassium channel membrane expression requires p38 mitogen-activated protein kinase phosphorylation.

    Science.gov (United States)

    Gururaj, Sushmitha; Fleites, John; Bhattacharjee, Arin

    2016-04-01

    p38 MAPK has long been understood as an inducible kinase under conditions of cellular stress, but there is now increasing evidence to support its role in the regulation of neuronal function. Several phosphorylation targets have been identified, an appreciable number of which are ion channels, implicating the possible involvement of p38 MAPK in neuronal excitability. The KNa channel Slack is an important protein to be studied as it is highly and ubiquitously expressed in DRG neurons and is important in the maintenance of their firing accommodation. We sought to examine if the Slack channel could be a substrate of p38 MAPK activity. First, we found that the Slack C-terminus contains two putative p38 MAPK phosphorylation sites that are highly conserved across species. Second, we show via electrophysiology experiments that KNa currents and further, Slack currents, are subject to tonic modulation by p38 MAPK. Third, biochemical approaches revealed that Slack channel regulation by p38 MAPK occurs through direct phosphorylation at the two putative sites of interaction, and mutating both sites prevented surface expression of Slack channels. Based on these results, we conclude that p38 MAPK is an obligate regulator of Slack channel function via the trafficking of channels into the membrane. The present study identifies Slack KNa channels as p38 MAPK substrates. PMID:26721627

  10. Initial Measurement of Intrapixel Variations in Back-Illuminated, High-Resistivity, p-Channel, Charge Coupled Device

    Science.gov (United States)

    Puls, Jason; Oluseyi, Hakeem M.

    2008-05-01

    In 1929 Edwin Hubble discovered the universe's expansion. Seventy years later it was unexpectedly found that the rate of expansion is accelerating due to some vast cosmic energy. This cosmic energy, apparently gravitationally repulsive and spread homogeneously through the universe, has come to be known as dark energy. To better understand this universal force, scientists utilize Type Ia supernovae and weak gravitational lensing as cosmological probes. Lawrence Berkeley National Laboratory (LBNL) is developing the Supernova Acceleration Probe (SNAP), a proposed space-based telescope that will be used to identify and measure supernovae and measure weak gravitational lensing signals across fifteen square degrees of the sky. The SNAP telescope will incorporate an innovative camera that consists of back-illuminated, high-resistivity, p-channel charged coupled devices (CCDs) for visible to near-infrared light detection. Presented are results obtained from the measurement and analysis of a 10.5 μm pixel pitch, 1.4k by 1.4k format, p-channel CCD fabricated on high-resistivity silicon at LBNL. The fully depleted device is 300 μm thick and backside illuminated. We report on the first measurement of the intrapixel sensitivity and spatial variations of these CCDs. We also report measurements of electric field distortions near the edges of the CCD active area.

  11. Predictions of charged charmonium-like structures with hidden-charm and open-strange channel

    CERN Document Server

    Chen, Dian-Yong; Matsuki, Takayuki

    2013-01-01

    We propose the initial single chiral particle emission (ISChE) mechanism, with which the hidden-charm di-kaon decays of higher charmonia and charmonium-like states are studied. Calculating the distributions of differential decay width, we obtain the line shape of the $J/\\psi K^+$ invariant mass spectrum of $\\psi_i\\to J/\\psi K^+K^-$, where $\\psi_i=\\psi(4415), Y(4660)$, and $\\psi(4790)$. Our numerical results show that there exist enhancement structures with both hidden-charm and open-strange, which are near the $D\\bar{D}_s^*/D^*\\bar{D}_s$ and $D^*\\bar{D}_s^*/\\bar{D}^*{D}_s^*$ thresholds. These charged charmonium-like structures predicted in this paper can be accessible at future experiment, especially BESIII, BelleII and SuperB.

  12. Exploiting MIC architectures for the simulation of channeling of charged particles in crystals

    Science.gov (United States)

    Bagli, Enrico; Karpusenko, Vadim

    2016-08-01

    Coherent effects of ultra-relativistic particles in crystals is an area of science under development. DYNECHARM + + is a toolkit for the simulation of coherent interactions between high-energy charged particles and complex crystal structures. The particle trajectory in a crystal is computed through numerical integration of the equation of motion. The code was revised and improved in order to exploit parallelization on multi-cores and vectorization of single instructions on multiple data. An Intel Xeon Phi card was adopted for the performance measurements. The computation time was proved to scale linearly as a function of the number of physical and virtual cores. By enabling the auto-vectorization flag of the compiler a three time speedup was obtained. The performances of the card were compared to the Dual Xeon ones.

  13. Arginine side chain interactions and the role of arginine as a gating charge carrier in voltage sensitive ion channels

    Science.gov (United States)

    Armstrong, Craig T.; Mason, Philip E.; Anderson, J. L. Ross; Dempsey, Christopher E.

    2016-02-01

    Gating charges in voltage-sensing domains (VSD) of voltage-sensitive ion channels and enzymes are carried on arginine side chains rather than lysine. This arginine preference may result from the unique hydration properties of the side chain guanidinium group which facilitates its movement through a hydrophobic plug that seals the center of the VSD, as suggested by molecular dynamics simulations. To test for side chain interactions implicit in this model we inspected interactions of the side chains of arginine and lysine with each of the 19 non-glycine amino acids in proteins in the protein data bank. The arginine guanidinium interacts with non-polar aromatic and aliphatic side chains above and below the guanidinium plane while hydrogen bonding with polar side chains is restricted to in-plane positions. In contrast, non-polar side chains interact largely with the aliphatic part of the lysine side chain. The hydration properties of arginine and lysine are strongly reflected in their respective interactions with non-polar and polar side chains as observed in protein structures and in molecular dynamics simulations, and likely underlie the preference for arginine as a mobile charge carrier in VSD.

  14. Channel-forming activity of syringopeptin 25A in mercury-supported phospholipid monolayers and negatively charged bilayers.

    Science.gov (United States)

    Becucci, Lucia; Toppi, Arianna; Fiore, Alberto; Scaloni, Andrea; Guidelli, Rolando

    2016-10-01

    Interactions of the cationic lipodepsipeptide syringopeptin 25A (SP25A) with mercury-supported dioleoylphosphatidylcholine (DOPC), dioleoylphosphatidylserine (DOPS) and dioeleoylphosphatidic acid (DOPA) self-assembled monolayers (SAMs) were investigated by AC voltammetry in 0.1M KCl at pH3, 5.4 and 6.8. SP25A targets and penetrates the DOPS SAM much more effectively than the other SAMs not only at pH6.8, where the DOPS SAM is negatively charged, but also at pH3, where it is positively charged just as SP25A. Similar investigations at tethered bilayer lipid membranes (tBLMs) consisting of a thiolipid called DPTL anchored to mercury, with a DOPS, DOPA or DOPC distal monolayer on top of it, showed that, at physiological transmembrane potentials, SP25A forms ion channels spanning the tBLM only if DOPS is the distal monolayer. The distinguishing chemical feature of the DOPS SAM is the ionic interaction between the protonated amino group of a DOPS molecule and the carboxylate group of an adjacent phospholipid molecule. Under the reasonable assumption that SP25A preferentially interacts with this ion pair, the selective lipodepsipeptide antimicrobial activity against Gram-positive bacteria may be tentatively explained by its affinity for similar protonated amino-carboxylate pairs, which are expected to be present in the peptide moieties of peptidoglycan strands. PMID:27322780

  15. 人鼻粘膜上皮细胞Na+通道的初步研究%Sodium channels in the apical membrane of human nasal epithelial cells

    Institute of Scientific and Technical Information of China (English)

    张欣欣; 郭永清; 董震; 杨占泉; 张文杰

    2001-01-01

    Objective To study the electrophysiological properties of sodium channels in the apical membrane of human nasal epithelial cells. Method Nasal epithelial cells of human inferior turbinate from patients with obstructive sleep apnea syndrome were cultured in serum free medium on collagen gel-coated membranes at an air-liquid interface and studied by a patch clamp technique. Results In cell-attached patches, a typical single channel current with a conductance of 21.09pS and reversal potential of -50.96 were recorded. The permeability ratio PNa/PK was more than 5.80. In the presence of 10-4 mmol/L amiloride in the pipette, the incidence of sodium channels decreased from 26.67% to 5.13%. This revealed that a population of channels were inhibited by amiloride at a dose of 10-4 mmol/L. Ca2+ at dose of 10-3 mmol/L did not influence the incidence of sodium channels. There was no obvious association between voltage and the open probability of the channels. Conclusions Our results indicate that most Na+ channels in cell-attached patches of human nasal epithelial cells are amiloride-sensitive and Na+ selective. Only a few channels are amiloride-insensitive. The channels were not activated by extracellular Ca2+ and the open probability followed a voltage-independent manner.%目的 明确人鼻粘膜上皮细胞Na+通道的特性,为研究Na+通道在鼻粘膜病理性改变及治疗中的作用奠定理论基础。 方法 利用膜片钳技术对经无血清气-液界面培养的鼻源性鼾症患者手术切除下鼻甲标本的鼻上皮细胞进行Na+通道基本特性研究。 结果 在细胞贴附式膜片上,可记录到典型的单通道电流,其电导为21.09pS,反转电位为-50.96mV,且77.78%反转电位5.80。在Na+通道抑制剂10-4 mmol/L Amiloride存在于电极液内时,Na+通道发生率从26.7%减少到5.13%(P0.05)。电压对开放概率无明显影响。 结论 在细胞贴附式膜片上,人鼻粘膜上皮细胞具有大

  16. Light doubly charged Higgs boson via the WW* channel at LHC

    Energy Technology Data Exchange (ETDEWEB)

    Kang, Zhaofeng [Korea Institute for Advanced Study, School of Physics, Seoul (Korea, Republic of); Peking University, Center for High-Energy Physics, Beijing (China); Li, Jinmian [University of Adelaide, Department of Physics, ARC Centre of Excellence for Particle Physics at the Terascale, Adelaide, SA (Australia); Chinese Academy of Sciences, State Key Laboratory of Theoretical Physics, Kavli Institute for Theoretical Physics China (KITPC), Institute of Theoretical Physics, Beijing (China); Li, Tianjun [Chinese Academy of Sciences, State Key Laboratory of Theoretical Physics, Kavli Institute for Theoretical Physics China (KITPC), Institute of Theoretical Physics, Beijing (China); University of Electronic Science and Technology of China, School of Physical Electronics, Chengdu (China); Liu, Yandong [Chinese Academy of Sciences, State Key Laboratory of Theoretical Physics, Kavli Institute for Theoretical Physics China (KITPC), Institute of Theoretical Physics, Beijing (China); Ning, Guo-Zhu [Peking University, Center for High-Energy Physics, Beijing (China)

    2015-12-15

    The doubly charged Higgs bosons H{sup ±±} searches at the large hadron collider (LHC) have been studied extensively and strong bound is available for H{sup ±±} dominantly decaying into a pair of same-sign di-leptons. In this paper we point out that there is a large cavity in the light H{sup ±±} mass region left unexcluded. In particular, H{sup ±±} can dominantly decay into WW or WW* (For instance, in the type-II seesaw mechanism the triplet acquires a vacuum expectation value around 1 GeV), and then it is found that H{sup ±±} with mass even below 2m{sub W} remains untouched by the current collider searches. Searching for such a H{sup ±±} at the LHC is the topic of this paper. We perform detailed signal and background simulation, especially including the non-prompt t anti t background which is the dominant one nevertheless ignored before. We show that such H{sup ±±} should be observable at the 14 TeV LHC with 10-30 fb{sup -1} integrated luminosity. (orig.)

  17. Light doubly charged Higgs boson via the WW{sup ∗} channel at LHC

    Energy Technology Data Exchange (ETDEWEB)

    Kang, Zhaofeng, E-mail: zhaofengkang@gmail.com [School of Physics, Korea Institute for Advanced Study, 130-722, Seoul (Korea, Republic of); Center for High-Energy Physics, Peking University, 100871, Beijing, People’s Republic of (China); Li, Jinmian, E-mail: phyljm@gmail.com [Department of Physics, ARC Centre of Excellence for Particle Physics at the Terascale, University of Adelaide, 5005, Adelaide, SA (Australia); State Key Laboratory of Theoretical Physics, Kavli Institute for Theoretical Physics China (KITPC), Institute of Theoretical Physics, Chinese Academy of Sciences, 100190, Beijing, People’s Republic of (China); Li, Tianjun, E-mail: tli@itp.ac.cn [State Key Laboratory of Theoretical Physics, Kavli Institute for Theoretical Physics China (KITPC), Institute of Theoretical Physics, Chinese Academy of Sciences, 100190, Beijing, People’s Republic of (China); School of Physical Electronics, University of Electronic Science and Technology of China, 610054, Chengdu, People’s Republic of (China); Liu, Yandong, E-mail: ydliu.hep@gmail.com [State Key Laboratory of Theoretical Physics, Kavli Institute for Theoretical Physics China (KITPC), Institute of Theoretical Physics, Chinese Academy of Sciences, 100190, Beijing, People’s Republic of (China); Ning, Guo-Zhu, E-mail: ngz@mail.nankai.edu.cn [Center for High-Energy Physics, Peking University, 100871, Beijing, People’s Republic of (China)

    2015-12-07

    The doubly charged Higgs bosons H{sup ±±} searches at the large hadron collider (LHC) have been studied extensively and strong bound is available for H{sup ±±} dominantly decaying into a pair of same-sign di-leptons. In this paper we point out that there is a large cavity in the light H{sup ±±} mass region left unexcluded. In particular, H{sup ±±} can dominantly decay into WW or WW{sup ∗} (For instance, in the type-II seesaw mechanism the triplet acquires a vacuum expectation value around 1 GeV), and then it is found that H{sup ±±} with mass even below 2m{sub W} remains untouched by the current collider searches. Searching for such a H{sup ±±} at the LHC is the topic of this paper. We perform detailed signal and background simulation, especially including the non-prompt tt{sup -bar} background which is the dominant one nevertheless ignored before. We show that such H{sup ±±} should be observable at the 14 TeV LHC with 10–30 fb{sup -1} integrated luminosity.

  18. Identification and Characterization of ProTx-III [μ-TRTX-Tp1a], a New Voltage-Gated Sodium Channel Inhibitor from Venom of the Tarantula Thrixopelma pruriens.

    Science.gov (United States)

    Cardoso, Fernanda C; Dekan, Zoltan; Rosengren, K Johan; Erickson, Andelain; Vetter, Irina; Deuis, Jennifer R; Herzig, Volker; Alewood, Paul F; King, Glenn F; Lewis, Richard J

    2015-08-01

    Spider venoms are a rich source of ion channel modulators with therapeutic potential. Given the analgesic potential of subtype-selective inhibitors of voltage-gated sodium (NaV) channels, we screened spider venoms for inhibitors of human NaV1.7 (hNaV1.7) using a high-throughput fluorescent assay. Here, we describe the discovery of a novel NaV1.7 inhibitor, μ-TRTX-Tp1a (Tp1a), isolated from the venom of the Peruvian green-velvet tarantula Thrixopelma pruriens. Recombinant and synthetic forms of this 33-residue peptide preferentially inhibited hNaV1.7 > hNaV1.6 > hNaV1.2 > hNaV1.1 > hNaV1.3 channels in fluorescent assays. NaV1.7 inhibition was diminished (IC50 11.5 nM) and the association rate decreased for the C-terminal acid form of Tp1a compared with the native amidated form (IC50 2.1 nM), suggesting that the peptide C terminus contributes to its interaction with hNaV1.7. Tp1a had no effect on human voltage-gated calcium channels or nicotinic acetylcholine receptors at 5 μM. Unlike most spider toxins that modulate NaV channels, Tp1a inhibited hNaV1.7 without significantly altering the voltage dependence of activation or inactivation. Tp1a proved to be analgesic by reversing spontaneous pain induced in mice by intraplantar injection in OD1, a scorpion toxin that potentiates hNaV1.7. The structure of Tp1a as determined using NMR spectroscopy revealed a classic inhibitor cystine knot (ICK) motif. The molecular surface of Tp1a presents a hydrophobic patch surrounded by positively charged residues, with subtle differences from other ICK spider toxins that might contribute to its different pharmacological profile. Tp1a may help guide the development of more selective and potent hNaV1.7 inhibitors for treatment of chronic pain.

  19. Identification and Characterization of ProTx-III [μ-TRTX-Tp1a], a New Voltage-Gated Sodium Channel Inhibitor from Venom of the Tarantula Thrixopelma pruriens.

    Science.gov (United States)

    Cardoso, Fernanda C; Dekan, Zoltan; Rosengren, K Johan; Erickson, Andelain; Vetter, Irina; Deuis, Jennifer R; Herzig, Volker; Alewood, Paul F; King, Glenn F; Lewis, Richard J

    2015-08-01

    Spider venoms are a rich source of ion channel modulators with therapeutic potential. Given the analgesic potential of subtype-selective inhibitors of voltage-gated sodium (NaV) channels, we screened spider venoms for inhibitors of human NaV1.7 (hNaV1.7) using a high-throughput fluorescent assay. Here, we describe the discovery of a novel NaV1.7 inhibitor, μ-TRTX-Tp1a (Tp1a), isolated from the venom of the Peruvian green-velvet tarantula Thrixopelma pruriens. Recombinant and synthetic forms of this 33-residue peptide preferentially inhibited hNaV1.7 > hNaV1.6 > hNaV1.2 > hNaV1.1 > hNaV1.3 channels in fluorescent assays. NaV1.7 inhibition was diminished (IC50 11.5 nM) and the association rate decreased for the C-terminal acid form of Tp1a compared with the native amidated form (IC50 2.1 nM), suggesting that the peptide C terminus contributes to its interaction with hNaV1.7. Tp1a had no effect on human voltage-gated calcium channels or nicotinic acetylcholine receptors at 5 μM. Unlike most spider toxins that modulate NaV channels, Tp1a inhibited hNaV1.7 without significantly altering the voltage dependence of activation or inactivation. Tp1a proved to be analgesic by reversing spontaneous pain induced in mice by intraplantar injection in OD1, a scorpion toxin that potentiates hNaV1.7. The structure of Tp1a as determined using NMR spectroscopy revealed a classic inhibitor cystine knot (ICK) motif. The molecular surface of Tp1a presents a hydrophobic patch surrounded by positively charged residues, with subtle differences from other ICK spider toxins that might contribute to its different pharmacological profile. Tp1a may help guide the development of more selective and potent hNaV1.7 inhibitors for treatment of chronic pain. PMID:25979003

  20. Regulation of voltage-gated sodium channel expression in cancer:hormones, growth factors and auto-regulation

    OpenAIRE

    Fraser, Scott P.; Ozerlat-Gunduz, Iley; Brackenbury, William J; Fitzgerald, Elizabeth M.; Campbell, Thomas M.; Coombes, R. Charles; Djamgoz, Mustafa B. A.

    2014-01-01

    Although ion channels are increasingly being discovered in cancer cells in vitro and in vivo, and shown to contribute to different aspects and stages of the cancer process, much less is known about the mechanisms controlling their expression. Here, we focus on voltage-gated Na(+) channels (VGSCs) which are upregulated in many types of carcinomas where their activity potentiates cell behaviours integral to the metastatic cascade. Regulation of VGSCs occurs at a hierarchy of levels from transcr...

  1. The insecticidal spider toxin SFI1 is a knottin peptide that blocks the pore of insect voltage-gated sodium channels via a large β-hairpin loop.

    Science.gov (United States)

    Bende, Niraj S; Dziemborowicz, Sławomir; Herzig, Volker; Ramanujam, Venkatraman; Brown, Geoffrey W; Bosmans, Frank; Nicholson, Graham M; King, Glenn F; Mobli, Mehdi

    2015-03-01

    Spider venoms contain a plethora of insecticidal peptides that act on neuronal ion channels and receptors. Because of their high specificity, potency and stability, these peptides have attracted much attention as potential environmentally friendly insecticides. Although many insecticidal spider venom peptides have been isolated, the molecular target, mode of action and structure of only a small minority have been explored. Sf1a, a 46-residue peptide isolated from the venom of the tube-web spider Segesteria florentina, is insecticidal to a wide range of insects, but nontoxic to vertebrates. In order to investigate its structure and mode of action, we developed an efficient bacterial expression system for the production of Sf1a. We determined a high-resolution solution structure of Sf1a using multidimensional 3D/4D NMR spectroscopy. This revealed that Sf1a is a knottin peptide with an unusually large β-hairpin loop that accounts for a third of the peptide length. This loop is delimited by a fourth disulfide bond that is not commonly found in knottin peptides. We showed, through mutagenesis, that this large loop is functionally critical for insecticidal activity. Sf1a was further shown to be a selective inhibitor of insect voltage-gated sodium channels, consistent with its 'depressant' paralytic phenotype in insects. However, in contrast to the majority of spider-derived sodium channel toxins that function as gating modifiers via interaction with one or more of the voltage-sensor domains, Sf1a appears to act as a pore blocker. PMID:25559770

  2. The tarantula toxin jingzhaotoxin-XI (κ-theraphotoxin-Cj1a) regulates the activation and inactivation of the voltage-gated sodium channel Nav1.5.

    Science.gov (United States)

    Tang, Cheng; Zhou, Xi; Huang, Yin; Zhang, Yunxiao; Hu, Zhaotun; Wang, Meichi; Chen, Ping; Liu, Zhonghua; Liang, Songping

    2014-12-15

    Specific peptide toxins interact with voltage-gated sodium channels by regulating the activation or inactivation of targeted channels. However, few toxins possessing dual effects have been identified. In the present study, we showed that jingzhaotoxin-XI/κ-theraphotoxin-Cj1a (JZTX-XI), a 34-residue peptide from the venom of the Chinese spider Chilobrachys jingzhao, inhibits the sodium conductance (IC50 = 124 ± 26 nM) and slows the fast inactivation (EC50 = 1.18 ± 0.2 μM) of Nav1.5 expressed in Chinese hamster ovary (CHO-K1) cells. JZTX-XI significantly shifted the activation to more depolarized voltages and decreased the deactivation of Nav1.5 currents upon extreme depolarization, but only slightly affected voltage-dependence of steady-state inactivation. In addition, JZTX-XI caused an approximately five-fold decrease in the rate of recovery from inactivation and an approximately 1.9-fold reduction in the closed-state inactivation rate. Our data suggest that JZTX-XI integrates the functions of site 3 toxins (α-scorpion toxins) with site 4 toxins (β-scorpion and spider toxins) by targeting multiple sites on Nav1.5. The unique properties displayed by JZTX-XI in its inhibitory activity on Nav1.5 suggest that its mechanism of action is distinct from those of site 3 and site 4 toxins, making JZTX-XI a useful probe for investigating the gating mechanism of Nav1.5 and toxin-channel interactions. PMID:25240294

  3. The chloride-channel blocker 9-anthracenecarboxylic acid reduces the nonlinear capacitance of prestin-associated charge movement.

    Science.gov (United States)

    Harasztosi, Csaba; Gummer, Anthony W

    2016-04-01

    The basis of the extraordinary sensitivity and frequency selectivity of the cochlea is a chloride-sensitive protein called prestin which can produce an electromechanical response and which resides in the basolateral plasma membrane of outer hair cells (OHCs). The compound 9-anthracenecarboxylic acid (9-AC), an inhibitor of chloride channels, has been found to reduce the electromechanical response of the cochlea and the OHC mechanical impedance. To elucidate these 9-AC effects, the functional electromechanical status of prestin was assayed by measuring the nonlinear capacitance of OHCs from the guinea-pig cochlea and of prestin-transfected human embryonic kidney 293 (HEK 293) cells. Extracellular application of 9-AC caused reversible, dose-dependent and chloride-sensitive reduction in OHC nonlinear charge transfer, Qmax . Prestin-transfected cells also showed reversible reduction in Qmax . For OHCs, intracellular 9-AC application as well as reduced intracellular pH had no detectable effect on the reduction in Qmax by extracellularly applied 9-AC. In the prestin-transfected cells, cytosolic application of 9-AC approximately halved the blocking efficacy of extracellularly applied 9-AC. OHC inside-out patches presented the whole-cell blocking characteristics. Disruption of the cytoskeleton by preventing actin polymerization with latrunculin A or by decoupling of spectrin from actin with diamide did not affect the 9-AC-evoked reduction in Qmax . We conclude that 9-AC acts on the electromechanical transducer principally by interaction with prestin rather than acting via the cytoskeleton, chloride channels or pH. The 9-AC block presents characteristics in common with salicylate, but is almost an order of magnitude faster. 9-AC provides a new tool for elucidating the molecular dynamics of prestin function. PMID:26869218

  4. Performance enhancement in p-channel charge-trapping flash memory devices with Si/Ge super-lattice channel and band-to-band tunneling induced hot-electron injection

    International Nuclear Information System (INIS)

    P-channel charge-trapping flash memory devices with Si, SiGe, and Si/Ge super-lattice channel are investigated in this work. A Si/Ge super-lattice structure with extremely low roughness and good crystal structure is obtained by precisely controlling the epitaxy thickness of Ge layer. Both programming and erasing (P/E) speeds are significantly improved by employing this Si/Ge super-lattice channel. Moreover, satisfactory retention and excellent endurance characteristics up to 106 P/E cycles with 3.8 V memory window show that the degradation on reliability properties is negligible when super-lattice channel is introduced. - Highlights: ► A super-lattice structure is proposed to introduce more Ge content into channel. ► Super-lattice structure possesses low roughness and good crystal structure. ► P-channel flash devices with Si, SiGe, and super-lattice channel are investigated. ► Programming/erasing speeds are significantly improved. ► Reliability properties can be kept for device with super-lattice channel

  5. Charge carrier recombination channels in the low-temperature phase of organic-inorganic lead halide perovskite thin films

    Directory of Open Access Journals (Sweden)

    Christian Wehrenfennig

    2014-08-01

    Full Text Available The optoelectronic properties of the mixed hybrid lead halide perovskite CH3NH3PbI3−xClx have been subject to numerous recent studies related to its extraordinary capabilities as an absorber material in thin film solar cells. While the greatest part of the current research concentrates on the behavior of the perovskite at room temperature, the observed influence of phonon-coupling and excitonic effects on charge carrier dynamics suggests that low-temperature phenomena can give valuable additional insights into the underlying physics. Here, we present a temperature-dependent study of optical absorption and photoluminescence (PL emission of vapor-deposited CH3NH3PbI3−xClx exploring the nature of recombination channels in the room- and the low-temperature phase of the material. On cooling, we identify an up-shift of the absorption onset by about 0.1 eV at about 100 K, which is likely to correspond to the known tetragonal-to-orthorhombic transition of the pure halide CH3NH3PbI3. With further decreasing temperature, a second PL emission peak emerges in addition to the peak from the room-temperature phase. The transition on heating is found to occur at about 140 K, i.e., revealing significant hysteresis in the system. While PL decay lifetimes are found to be independent of temperature above the transition, significantly accelerated recombination is observed in the low-temperature phase. Our data suggest that small inclusions of domains adopting the room-temperature phase are responsible for this behavior rather than a spontaneous increase in the intrinsic rate constants. These observations show that even sparse lower-energy sites can have a strong impact on material performance, acting as charge recombination centres that may detrimentally affect photovoltaic performance but that may also prove useful for optoelectronic applications such as lasing by enhancing population inversion.

  6. Charged residues distribution modulates selectivity of the open state of human isoforms of the voltage dependent anion-selective channel.

    Science.gov (United States)

    Amodeo, Giuseppe Federico; Scorciapino, Mariano Andrea; Messina, Angela; De Pinto, Vito; Ceccarelli, Matteo

    2014-01-01

    Voltage Dependent Anion-selective Channels (VDACs) are pore-forming proteins located in the outer mitochondrial membrane. They are responsible for the access of ions and energetic metabolites into the inner membrane transport systems. Three VDAC isoforms exist in mammalian, but their specific role is unknown. In this work we have performed extensive (overall ∼5 µs) Molecular Dynamics (MD) simulations of the human VDAC isoforms to detect structural and conformational variations among them, possibly related to specific functional roles of these proteins. Secondary structure analysis of the N-terminal domain shows a high similarity among the three human isoforms of VDAC but with a different plasticity. In particular, the N-terminal domain of the hVDAC1 is characterized by a higher plasticity, with a ∼20% occurrence for the 'unstructured' conformation throughout the folded segment, while hVDAC2, containing a peculiar extension of 11 amino acids at the N-terminal end, presents an additional 310-helical folded portion comprising residues 10' to 3, adhering to the barrel wall. The N-terminal sequences of hVDAC isoforms are predicted to have a low flexibility, with possible consequences in the dynamics of the human VDACs. Clear differences were found between hVDAC1 and hVDAC3 against hVDAC2: a significantly modified dynamics with possible important consequence on the voltage-gating mechanism. Charge distribution inside and at the mouth of the pore is responsible for a different preferential localization of ions with opposite charge and provide a valuable rationale for hVDAC1 and hVDAC3 having a Cl-/K+ selectivity ratio of 1.8, whereas hVDAC2 of 1.4. Our conclusion is that hVDAC isoforms, despite sharing a similar scaffold, have modified working features and a biological work is now requested to give evidence to the described dissimilarities. PMID:25084457

  7. Charged residues distribution modulates selectivity of the open state of human isoforms of the voltage dependent anion-selective channel.

    Directory of Open Access Journals (Sweden)

    Giuseppe Federico Amodeo

    Full Text Available Voltage Dependent Anion-selective Channels (VDACs are pore-forming proteins located in the outer mitochondrial membrane. They are responsible for the access of ions and energetic metabolites into the inner membrane transport systems. Three VDAC isoforms exist in mammalian, but their specific role is unknown. In this work we have performed extensive (overall ∼5 µs Molecular Dynamics (MD simulations of the human VDAC isoforms to detect structural and conformational variations among them, possibly related to specific functional roles of these proteins. Secondary structure analysis of the N-terminal domain shows a high similarity among the three human isoforms of VDAC but with a different plasticity. In particular, the N-terminal domain of the hVDAC1 is characterized by a higher plasticity, with a ∼20% occurrence for the 'unstructured' conformation throughout the folded segment, while hVDAC2, containing a peculiar extension of 11 amino acids at the N-terminal end, presents an additional 310-helical folded portion comprising residues 10' to 3, adhering to the barrel wall. The N-terminal sequences of hVDAC isoforms are predicted to have a low flexibility, with possible consequences in the dynamics of the human VDACs. Clear differences were found between hVDAC1 and hVDAC3 against hVDAC2: a significantly modified dynamics with possible important consequence on the voltage-gating mechanism. Charge distribution inside and at the mouth of the pore is responsible for a different preferential localization of ions with opposite charge and provide a valuable rationale for hVDAC1 and hVDAC3 having a Cl-/K+ selectivity ratio of 1.8, whereas hVDAC2 of 1.4. Our conclusion is that hVDAC isoforms, despite sharing a similar scaffold, have modified working features and a biological work is now requested to give evidence to the described dissimilarities.

  8. Charge carrier recombination channels in the low-temperature phase of organic-inorganic lead halide perovskite thin films

    Science.gov (United States)

    Wehrenfennig, Christian; Liu, Mingzhen; Snaith, Henry J.; Johnston, Michael B.; Herz, Laura M.

    2014-08-01

    The optoelectronic properties of the mixed hybrid lead halide perovskite CH3NH3PbI3-xClx have been subject to numerous recent studies related to its extraordinary capabilities as an absorber material in thin film solar cells. While the greatest part of the current research concentrates on the behavior of the perovskite at room temperature, the observed influence of phonon-coupling and excitonic effects on charge carrier dynamics suggests that low-temperature phenomena can give valuable additional insights into the underlying physics. Here, we present a temperature-dependent study of optical absorption and photoluminescence (PL) emission of vapor-deposited CH3NH3PbI3-xClx exploring the nature of recombination channels in the room- and the low-temperature phase of the material. On cooling, we identify an up-shift of the absorption onset by about 0.1 eV at about 100 K, which is likely to correspond to the known tetragonal-to-orthorhombic transition of the pure halide CH3NH3PbI3. With further decreasing temperature, a second PL emission peak emerges in addition to the peak from the room-temperature phase. The transition on heating is found to occur at about 140 K, i.e., revealing significant hysteresis in the system. While PL decay lifetimes are found to be independent of temperature above the transition, significantly accelerated recombination is observed in the low-temperature phase. Our data suggest that small inclusions of domains adopting the room-temperature phase are responsible for this behavior rather than a spontaneous increase in the intrinsic rate constants. These observations show that even sparse lower-energy sites can have a strong impact on material performance, acting as charge recombination centres that may detrimentally affect photovoltaic performance but that may also prove useful for optoelectronic applications such as lasing by enhancing population inversion.

  9. Multi-country Survey Revealed Prevalent and Novel F1534S Mutation in Voltage-Gated Sodium Channel (VGSC Gene in Aedes albopictus.

    Directory of Open Access Journals (Sweden)

    Jiabao Xu

    2016-05-01

    Full Text Available Aedes albopictus is an important dengue vector because of its aggressive biting behavior and rapid spread out of its native home range in Southeast Asia. Pyrethroids are widely used for adult mosquito control, and resistance to pyrethroids should be carefully monitored because vector control is the only effective method currently available to prevent dengue transmission. The voltage-gated sodium channel gene is the target site of pyrethroids, and mutations in this gene cause knockdown resistance (kdr. Previous studies reported various mutations in the voltage-gated sodium channel (VGSC gene, but the spatial distribution of kdr mutations in Ae. albopictus has not been systematically examined, and the association between kdr mutation and phenotypic resistance has not been established.A total of 597 Ae. albopictus individuals from 12 populations across Asia, Africa, America and Europe were examined for mutations in the voltage-gated sodium channel gene. Three domains for a total of 1,107 bp were sequenced for every individual. Two populations from southern China were examined for pyrethroid resistance using the World Health Organization standard tube bioassay, and the association between kdr mutations and phenotypic resistance was tested.A total of 29 synonymous mutations were found across domain II, III and IV of the VGSC gene. Non-synonymous mutations in two codons of the VGSC gene were detected in 5 populations from 4 countries. A novel mutation at 1532 codon (I1532T was found in Rome, Italy with a frequency of 19.7%. The second novel mutation at codon 1534 (F1534S was detected in southern China and Florida, USA with a frequency ranging from 9.5-22.6%. The WHO insecticide susceptibility bioassay found 90.1% and 96.1% mortality in the two populations from southern China, suggesting resistance and probable resistance. Positive association between kdr mutations with deltamethrin resistance was established in these two populations.Two novel kdr

  10. Sodium chloride salinity reduces Cd uptake by edible amaranth (Amaranthus mangostanus L.) via competition for Ca channels.

    Science.gov (United States)

    Mei, XiuQin; Li, SongSong; Li, QuSheng; Yang, YuFeng; Luo, Xuan; He, BaoYan; Li, Hui; Xu, ZhiMin

    2014-07-01

    Soil salinity is known to enhance cadmium (Cd) accumulation in crops. However, the mechanism by which this occurs independent of the surrounding soil remains unclear. In this study, root adsorption and uptake of salt cations and Cd by edible amaranth under NaCl salinity stress were investigated in hydroponic cultures with 0, 40, 80, 120, and 160mM of NaCl and 27nM Cd. The dominant Cd species in the nutrient solution changed from free Cd(2+) to Cd chlorocomplexes as NaCl salinity increased. High salinity significantly reduced K, Ca, and Cd root adsorption and K, Ca, Mg, and Cd uptake. High salinity decreased root adsorption of Cd by 43 and 58 percent and Cd uptake by 32 and 36 percent in salt-tolerant and salt-sensitive cultivars, respectively. Transformation of Cd from free ion to chlorocomplexes is unlikely to have significantly affected Cd uptake by the plant because of the very low Cd concentrations involved. Application of Ca ion channel blocker significantly reduced Na, K, Ca, Mg, and Cd uptake by the roots, while blocking K ion channels significantly reduced Na and K uptake but not Ca, Mg, and Cd uptake. These results suggest that Na was absorbed by the roots through both Ca and K ion channels, while Cd was absorbed by the roots mainly through Ca ion channels and not K ion channels. Salinity caused a greater degree of reduction in Cd adsorption and uptake in the salt-sensitive cultivar than in the salt-tolerant cultivar. Thus, competition between Na and Cd for Ca ion channels can reduce Cd uptake at very low Cd concentrations in the nutrient solution.

  11. Polyvinylpyrrolidone-sodium dodecylsulfate complex is a family of pseudo-polyanions with different charge densities: Evidence from capillary electrophoresis, capillary viscosimetry and conductometry.

    Science.gov (United States)

    Wu, Yefan; Chen, Jie; Fang, Yun; Zhu, Meng

    2016-10-01

    Accordance with the previously supposed polyelectrolyte-like behaviour of neutral polymer-anionic surfactant complexes, direct evidence for the formation of the pseudo-polyanions in polyvinylpyrrolidone (PVP)-sodium dodecylsulfate (SDS) solution is put forward in this paper by capillary electrophoresis (CE) experiments in assistance with capillary viscosimetry and conductometry. The contradictory phenomena of the absolute value of relative electrophoretic mobility (re) increasing while the ionization degree (α) decreasing with the increasing specific clusterization [Г] in aqueous PVP-SDS solution are explained by the finding that the PVP-SDS complex is eventually a family of PVP-SDS pseudo-polyanions with different charge densities. And it is found countercations playing an important role in the formation of the PVP-SDS pseudo-polyanions in virtue of bridge effect. PMID:27348481

  12. Molecular determinants of voltage-gated sodium channel regulation by the Nedd4/Nedd4-like proteins

    DEFF Research Database (Denmark)

    Rougier, Jean-Sébastien; van Bemmelen, Miguel X; Bruce, M Christine;

    2004-01-01

    The voltage-gated Na(+) channels (Na(v)) form a family composed of 10 genes. The COOH termini of Na(v) contain a cluster of amino acids that are nearly identical among 7 of the 10 members. This COOH-terminal sequence, PPSYDSV, is a PY motif known to bind to WW domains of E3 protein...

  13. Molecular basis of the inhibition of the fast inactivation of voltage-gated sodium channel Nav1.5 by tarantula toxin Jingzhaotoxin-II.

    Science.gov (United States)

    Huang, Ying; Zhou, Xi; Tang, Cheng; Zhang, Yunxiao; Tao, Huai; Chen, Ping; Liu, Zhonghua

    2015-06-01

    Jingzhaotoxin-II (JZTX-II) is a 32-residue peptide from the Chinese tarantula Chilobrachys jingzhao venom, and preferentially inhibits the fast inactivation of the voltage-gated sodium channels (VGSCs) in rat cardiac myocytes. In the present study, we elucidated the action mechanism of JZTX-II inhibiting hNav1.5, a VGSC subtype mainly distributed in human cardiac myocytes. Among the four VGSC subtypes tested, hNav1.5 was the most sensitive to JZTX-II (EC50=125±4nM). Although JZTX-II had little or no effect on steady-state inactivation of the residual currents conducted by hNav1.5, it caused a 10mV hyperpolarized shift of activation. Moreover, JZTX-II increased the recovery rate of hNav1.5 channels, which should lead to a shorter transition from the inactivation to closed state. JZTX-II dissociated from toxin-channel complex via extreme depolarization and subsequently rebound to the channel upon repolarization. Mutagenesis analyses showed that the domain IV (DIV) voltage-sensor domain (VSD) was critical for JZTX-II binding to hNav1.5 and some mutations located in S1-S2 and S3-S4 extracellular loops of hNav1.5 DIV additively reduced the toxin sensitivity of hNav1.5. Our data identified the mechanism underlying JZTX-II inhibiting hNav1.5, similar to scorpion α-toxins, involving binding to neurotoxin receptor site 3. PMID:25817910

  14. A proton leak current through the cardiac sodium channel is linked to mixed arrhythmia and the dilated cardiomyopathy phenotype.

    Directory of Open Access Journals (Sweden)

    Pascal Gosselin-Badaroudine

    Full Text Available Cardiac Na(+ channels encoded by the SCN5A gene are essential for initiating heart beats and maintaining a regular heart rhythm. Mutations in these channels have recently been associated with atrial fibrillation, ventricular arrhythmias, conduction disorders, and dilated cardiomyopathy (DCM.We investigated a young male patient with a mixed phenotype composed of documented conduction disorder, atrial flutter, and ventricular tachycardia associated with DCM. Further family screening revealed DCM in the patient's mother and sister and in three of the mother's sisters. Because of the complex clinical phenotypes, we screened SCN5A and identified a novel mutation, R219H, which is located on a highly conserved region on the fourth helix of the voltage sensor domain of Na(v1.5. Three family members with DCM carried the R219H mutation.The wild-type (WT and mutant Na(+ channels were expressed in a heterologous expression system, and intracellular pH (pHi was measured using a pH-sensitive electrode. The biophysical characterization of the mutant channel revealed an unexpected selective proton leak with no effect on its biophysical properties. The H(+ leak through the mutated Na(v1.5 channel was not related to the Na(+ permeation pathway but occurred through an alternative pore, most probably a proton wire on the voltage sensor domain.We propose that acidification of cardiac myocytes and/or downstream events may cause the DCM phenotype and other electrical problems in affected family members. The identification of this clinically significant H(+ leak may lead to the development of more targeted treatments.

  15. Expressions for Form Factors for Inelastic Scattering and Charge Exchange in Plane-Wave, Distorted-Wave, and Coupled-Channels Reaction Formalisms

    Energy Technology Data Exchange (ETDEWEB)

    Dietrich, F S

    2006-09-25

    This document is intended to facilitate calculation of inelastic scattering and charge-exchange cross sections in a variety of reaction models, including the plane-wave and distorted-wave approximations and the full coupled-channels treatments. Expressions are given for the coupling potentials between the relevant channels in both coordinate and momentum space. In particular, it is expected that the plane-wave calculations should be useful as a check on the correctness of coupled-channels calculations. The Fourier transform methods used to calculate the plane-wave approximation cross sections are also intended to be used to generate the transition potentials for coupled-channels codes, using a folding model with local effective interactions. Specific expressions are given for calculating transition densities for the folding model in the random phase approximation (RPA).

  16. The role of electronic symmetry in charge-transfer-to-solvent reactions: Quantum nonadiabatic computer simulation of photoexcited sodium anions

    OpenAIRE

    Smallwood, C J; Bosma, W B; Larsen, R E; Schwartz, Benjamin J.

    2003-01-01

    Since charge-transfer-to-solvent (CTTS) reactions represent the simplest class of solvent-driven electron transfer reactions, there has been considerable interest in understanding the solvent motions responsible for electron ejection. The major question that we explore in this paper is what role the symmetry of the electronic states plays in determining the solvent motions that account for CTTS. To this end, we have performed a series of one-electron mixed quantum/classical nonadiabatic molec...

  17. Characterization of Disopyramide derivative ADD424042 as a non-cardiotoxic neuronal sodium channel blocker with broad-spectrum anticonvulsant activity in rodent seizure models.

    Science.gov (United States)

    Król, Marek; Ufnal, Marcin; Szulczyk, Bartłomiej; Podsadni, Piotr; Drapała, Adrian; Turło, Jadwiga; Dawidowski, Maciej

    2016-01-01

    It was reported that antiarrhythmic drugs (AADs) can be useful in controlling refractory seizures in humans or in enhancing the action of antiepileptic drugs (AEDs) in animal models. Disopyramide phosphate (DISO) is an AAD that blocks sodium channels in cardiac myocytes. We evaluated a DISO derivative, 2-(2-chlorophenyl)-2-(pyridin-2-yl)acetamide (ADD424042) for its anticonvulsant activity in a battery of rodent models of epileptic seizures. The compound displayed a broad spectrum of activity in the 'classical' models as well as in the models of pharmacoresistant seizures. Furthermore, ADD424042 showed good therapeutic indices between the anticonvulsant activity and the motor impairment. On the contrary, no anticonvulsant effects but severe lethality were observed in the primary anticonvulsant testing of the parent DISO. By performing the whole-cell voltage-clamp experiments in dispersed cortical neurons we demonstrated that ADD424042 decreased the maximal amplitude of voltage-gated sodium channels with an IC50 value in nM range. Moreover, the compound enhanced use-dependent block and decreased excitability in pyramidal neurons in the current-clamp experiments in cortical slices. Importantly, we found that ADD424042 possessed either no, or very small cardiotoxic effect. In contrast to DISO, ADD424042 did not produce any apparent changes in electrocardiogram (ECG) and arterial blood pressure recordings. ADD424042 had no effect on QT and corrected QT intervals, at a dose which was 15 times higher than ED50 for the anticonvulsant effect in the MES model. Taken together, these data suggest that ADD424042 has the potential to become a lead structure for novel broadly acting AEDs with wide margin of cardiac safety.

  18. A Common Polymorphism of the Human Cardiac Sodium Channel Alpha Subunit (SCN5A Gene Is Associated with Sudden Cardiac Death in Chronic Ischemic Heart Disease.

    Directory of Open Access Journals (Sweden)

    Boglárka Marcsa

    Full Text Available Cardiac death remains one of the leading causes of mortality worldwide. Recent research has shed light on pathophysiological mechanisms underlying cardiac death, and several genetic variants in novel candidate genes have been identified as risk factors. However, the vast majority of studies performed so far investigated genetic associations with specific forms of cardiac death only (sudden, arrhythmogenic, ischemic etc.. The aim of the present investigation was to find a genetic marker that can be used as a general, powerful predictor of cardiac death risk. To this end, a case-control association study was performed on a heterogeneous cohort of cardiac death victims (n=360 and age-matched controls (n=300. Five single nucleotide polymorphisms (SNPs from five candidate genes (beta2 adrenergic receptor, nitric oxide synthase 1 adaptor protein, ryanodine receptor 2, sodium channel type V alpha subunit and transforming growth factor-beta receptor 2 that had previously been shown to associate with certain forms of cardiac death were genotyped using sequence-specific real-time PCR probes. Logistic regression analysis revealed that the CC genotype of the rs11720524 polymorphism in the SCN5A gene encoding a subunit of the cardiac voltage-gated sodium channel occurred more frequently in the highly heterogeneous cardiac death cohort compared to the control population (p=0.019, odds ratio: 1.351. A detailed subgroup analysis uncovered that this effect was due to an association of this variant with cardiac death in chronic ischemic heart disease (p=0.012, odds ratio = 1.455. None of the other investigated polymorphisms showed association with cardiac death in this context. In conclusion, our results shed light on the role of this non-coding polymorphism in cardiac death in ischemic cardiomyopathy. Functional studies are needed to explore the pathophysiological background of this association.

  19. Donnan effect on chloride ion distribution as a determinant of body fluid composition that allows action potentials to spread via fast sodium channels

    Directory of Open Access Journals (Sweden)

    Kurbel Sven

    2011-05-01

    Full Text Available Abstract Proteins in any solution with a pH value that differs from their isoelectric point exert both an electric Donnan effect (DE and colloid osmotic pressure. While the former alters the distribution of ions, the latter forces water diffusion. In cells with highly Cl--permeable membranes, the resting potential is more dependent on the cytoplasmic pH value, which alters the Donnan effect of cell proteins, than on the current action of Na/K pumps. Any weak (positive or negative electric disturbances of their resting potential are quickly corrected by chloride shifts. In many excitable cells, the spreading of action potentials is mediated through fast, voltage-gated sodium channels. Tissue cells share similar concentrations of cytoplasmic proteins and almost the same exposure to the interstitial fluid (IF chloride concentration. The consequence is that similar intra- and extra-cellular chloride concentrations make these cells share the same Nernst value for Cl-. Further extrapolation indicates that cells with the same chloride Nernst value and high chloride permeability should have similar resting membrane potentials, more negative than -80 mV. Fast sodium channels require potassium levels >20 times higher inside the cell than around it, while the concentration of Cl- ions needs to be >20 times higher outside the cell. When osmotic forces, electroneutrality and other ions are all taken into account, the overall osmolarity needs to be near 280 to 300 mosm/L to reach the required resting potential in excitable cells. High plasma protein concentrations keep the IF chloride concentration stable, which is important in keeping the resting membrane potential similar in all chloride-permeable cells. Probable consequences of this concept for neuron excitability, erythrocyte membrane permeability and several features of circulation design are briefly discussed.

  20. Characterization of Disopyramide derivative ADD424042 as a non-cardiotoxic neuronal sodium channel blocker with broad-spectrum anticonvulsant activity in rodent seizure models.

    Science.gov (United States)

    Król, Marek; Ufnal, Marcin; Szulczyk, Bartłomiej; Podsadni, Piotr; Drapała, Adrian; Turło, Jadwiga; Dawidowski, Maciej

    2016-01-01

    It was reported that antiarrhythmic drugs (AADs) can be useful in controlling refractory seizures in humans or in enhancing the action of antiepileptic drugs (AEDs) in animal models. Disopyramide phosphate (DISO) is an AAD that blocks sodium channels in cardiac myocytes. We evaluated a DISO derivative, 2-(2-chlorophenyl)-2-(pyridin-2-yl)acetamide (ADD424042) for its anticonvulsant activity in a battery of rodent models of epileptic seizures. The compound displayed a broad spectrum of activity in the 'classical' models as well as in the models of pharmacoresistant seizures. Furthermore, ADD424042 showed good therapeutic indices between the anticonvulsant activity and the motor impairment. On the contrary, no anticonvulsant effects but severe lethality were observed in the primary anticonvulsant testing of the parent DISO. By performing the whole-cell voltage-clamp experiments in dispersed cortical neurons we demonstrated that ADD424042 decreased the maximal amplitude of voltage-gated sodium channels with an IC50 value in nM range. Moreover, the compound enhanced use-dependent block and decreased excitability in pyramidal neurons in the current-clamp experiments in cortical slices. Importantly, we found that ADD424042 possessed either no, or very small cardiotoxic effect. In contrast to DISO, ADD424042 did not produce any apparent changes in electrocardiogram (ECG) and arterial blood pressure recordings. ADD424042 had no effect on QT and corrected QT intervals, at a dose which was 15 times higher than ED50 for the anticonvulsant effect in the MES model. Taken together, these data suggest that ADD424042 has the potential to become a lead structure for novel broadly acting AEDs with wide margin of cardiac safety. PMID:26441377

  1. Altered expression of renal bumetanide-sensitive sodium-pota-ssium-2 chloride cotransporter and Cl- channel -K2 gene in angiotensin Ⅱ-infused hypertensive rats

    Institute of Scientific and Technical Information of China (English)

    YE Tao; LIU Zhi-quan; SUN Chao-feng; ZHENG Yong; MA Ai-qun; FANG Yuan

    2005-01-01

    Background Little information is available regarding the effect of angiotensin Ⅱ (Ang Ⅱ) on the bumetanide-sensitive sodium-potassium-2 chloride cotransporter (NKCC2), the thiazide-sensitive sodium-chloride cotransporter (NCC), and the Cl- channel (CLC)-K2 at both mRNA and protein expression level in Ang Ⅱ-induced hypertensive rats. This study was conducted to investigate the influence of Ang Ⅱ with chronic subpressor infusion on nephron-specific gene expression of NKCC2, NCC and CLC-K2. Results Ang Ⅱ significantly increased blood pressure and up-regulated NKCC2 mRNA and protein expression in the kidney. Expression of CLC-K2 mRNA in the kidney increased 1.6 fold (P<0.05).There were no changes in NCC mRNA or protein expression in AngII-treated rats versus control. Conclusions Chronic subpressor Ang Ⅱ infusion can significantly alter NKCC2 and CLC-K2 mRNA expression in the kidney, and protein abundance of NKCC2 in kidney is positively regulated by Ang Ⅱ. These effects may contribute to enhanced renal Na+ and Cl- reabsorption in response to Ang Ⅱ.

  2. Mice with an NaV1.4 sodium channel null allele have latent myasthenia, without susceptibility to periodic paralysis.

    Science.gov (United States)

    Wu, Fenfen; Mi, Wentao; Fu, Yu; Struyk, Arie; Cannon, Stephen C

    2016-06-01

    Over 60 mutations of SCN4A encoding the NaV1.4 sodium channel of skeletal muscle have been identified in patients with myotonia, periodic paralysis, myasthenia, or congenital myopathy. Most mutations are missense with gain-of-function defects that cause susceptibility to myotonia or periodic paralysis. Loss-of-function from enhanced inactivation or null alleles is rare and has been associated with myasthenia and congenital myopathy, while a mix of loss and gain of function changes has an uncertain relation to hypokalaemic periodic paralysis. To better define the functional consequences for a loss-of-function, we generated NaV1.4 null mice by deletion of exon 12. Heterozygous null mice have latent myasthenia and a right shift of the force-stimulus relation, without evidence of periodic paralysis. Sodium current density was half that of wild-type muscle and no compensation by retained expression of the foetal NaV1.5 isoform was detected. Mice null for NaV1.4 did not survive beyond the second postnatal day. This mouse model shows remarkable preservation of muscle function and viability for haploinsufficiency of NaV1.4, as has been reported in humans, with a propensity for pseudo-myasthenia caused by a marginal Na(+) current density to support sustained high-frequency action potentials in muscle. PMID:27048647

  3. Antagonist action of progesterone at σ-receptors in the modulation of voltage-gated sodium channels

    OpenAIRE

    Johannessen, Molly; Fontanilla, Dominique; Mavlyutov, Timur; Ruoho, Arnold E.; Jackson, Meyer B.

    2010-01-01

    σ-Receptors are integral membrane proteins that have been implicated in a number of biological functions, many of which involve the modulation of ion channels. A wide range of synthetic ligands activate σ-receptors, but endogenous σ-receptor ligands have proven elusive. One endogenous ligand, dimethyltryptamine (DMT), has been shown to act as a σ-receptor agonist. Progesterone and other steroids bind σ-receptors, but the functional consequences of these interactions are unclear. Here we inves...

  4. Regulation of voltage-gated sodium channel expression in cancer: hormones, growth factors and auto-regulation.

    Science.gov (United States)

    Fraser, Scott P; Ozerlat-Gunduz, Iley; Brackenbury, William J; Fitzgerald, Elizabeth M; Campbell, Thomas M; Coombes, R Charles; Djamgoz, Mustafa B A

    2014-03-19

    Although ion channels are increasingly being discovered in cancer cells in vitro and in vivo, and shown to contribute to different aspects and stages of the cancer process, much less is known about the mechanisms controlling their expression. Here, we focus on voltage-gated Na(+) channels (VGSCs) which are upregulated in many types of carcinomas where their activity potentiates cell behaviours integral to the metastatic cascade. Regulation of VGSCs occurs at a hierarchy of levels from transcription to post-translation. Importantly, mainstream cancer mechanisms, especially hormones and growth factors, play a significant role in the regulation. On the whole, in major hormone-sensitive cancers, such as breast and prostate cancer, there is a negative association between genomic steroid hormone sensitivity and functional VGSC expression. Activity-dependent regulation by positive feedback has been demonstrated in strongly metastatic cells whereby the VGSC is self-sustaining, with its activity promoting further functional channel expression. Such auto-regulation is unlike normal cells in which activity-dependent regulation occurs mostly via negative feedback. Throughout, we highlight the possible clinical implications of functional VGSC expression and regulation in cancer. PMID:24493753

  5. Membrane conductances involved in amplification of small signals by sodium channels in photoreceptors of drone honey bee.

    Science.gov (United States)

    Vallet, A M; Coles, J A; Eilbeck, J C; Scott, A C

    1992-10-01

    1. Voltage signals of about 1 mV evoked in photoreceptors of the drone honey bee by shallow modulation of a background illumination of an intensity useful for behaviour are thought to be amplified by voltage-dependent Na+ channels. To elucidate the roles of the various membrane conductances in this amplification we have studied the effects of the Na+ channel blocker tetrodotoxin (TTX) and various putative K+ channel blockers on the membrane potential, Vm. 2. Superfusion of a slice of retina with 0.5-10 mM-4-aminopyridine (4-AP) depolarized the membrane and, in fifty of sixty-three cells induced repetitive action potentials. Ionophoretic injection of tetraethylammonium produced similar effects. 3. In order to measure the depolarization caused by 4-AP, action potentials were prevented by application of TTX: 4-AP was applied when the membrane was depolarized to different levels by light. 4-AP induced an additional depolarization at all membrane potentials tested (-64 to -27 mV). We conclude that there are 4-AP-sensitive K+ channels that are open at constant voltage over this range. 4. 4-AP slowed down the recovery phase of the action potential induced by a light flash by a factor that ranged from 0.51 to 0.16. This reduction could be accounted for by the reduction in a voltage-independent K+ conductance estimated from the steady-state depolarization. 5. After the voltage-gated Na+ channels had been blocked by TTX, exposure to 4-AP further changed the amplitude of the response to a small (approximately 10%) decremental light stimulus. The change was an increase when the background illumination brought Vm to potentials more negative than about -40 mV; it was a decrease when Vm > -40 mV. The data could be fitted by a circuit representation of the membrane with a light-activated conductance and a K+ conductance (EK = -66 mV) that was partly blocked by 4-AP. The voltage range studied was from -52 to -27 mV; neither conductance in the model was voltage dependent. 6. The

  6. Development of analysis and reconstruction tools in Opera and analysis of {tau} {yields} 3 charged hadrons channel; Developpement des outils d'analyse et de reconstruction dans OPERA et analyse du canal {tau} {yields} 3 hadrons charges

    Energy Technology Data Exchange (ETDEWEB)

    Lavy, M

    2004-07-01

    OPERA aims to prove the existence of {nu}{sub {mu}} {yields} {nu}{sub {tau}} oscillation by a direct observation of {nu}{sub {tau}} appearance in a {nu}{sub {mu}} beam. To achieve this goal, a pure {nu}{sub {mu}} beam is produced at CERN and directed towards the Gran Sasso underground laboratory where the OPERA detector is located. The nuclear emulsions composing the detector have a very high degree of accuracy in position ({mu}m) and should allow {tau} lepton detection produced via {nu}{sub {tau}} charged current interaction. The emulsions analysis is thus a key point of the OPERA experiment. The development of simulation and reconstruction software is a part of this thesis work. In an other part of this thesis, it is shown that with a suitable kinematic analysis, the 3 charged hadrons tau decay channel can be used as any tau decay channels in the OPERA data analysis. (author)

  7. Augmented activity of the pelvic nerve afferent mediated by TRP channels in dextran sulfate sodium (DSS)-induced colitis of rats.

    Science.gov (United States)

    Makimura, Yukitoshi; Ito, Koichi; Kuwahara, Masayoshi; Tsubone, Hirokazu

    2012-08-01

    Enteritis has been recognized as a major symptom in domestic animals and human patients suffering from feed and food poisonings. The aim of the present study was to clarify the excitatory mechanism of the pelvic nerve afferent which may influence the occurrence of enteritis in response to nociceptive chemical stimuli of the colon in normal and abnormal rats with colitis induced by dextran sulfate sodium (DSS). The pelvic nerve afferent activity was markedly increased by colonic instillation of solution (0.5 ml) of acetic acid (5-25%) and capsaicin (100 μg/ml). The nerve activity was augmented by colonic instillation of capsaicin to a greater extent in rats with DSS-induced colitis than in normal control rats. This augmented activity by capsaicin was more prominent at one day (DSS-1) than at 8 day (DSS-8) after the administration of DSS. The increased nerve activity caused by capsaicin in DSS-1 and DSS-8 was significantly inhibited by pretreatment with ruthenium red, which is a nonselective inhibitor of TRP channels of unmyelinated C-fibers (nociceptors). In conclusion, it was elucidated that the nociceptive function of the pelvic nerve was largely elevated at one day after DSS-induced colitis and such increased function was mostly mediated by TRP channels.

  8. L925I mutation in the Para-type sodium channel is associated with pyrethroid resistance in Triatoma infestans from the Gran Chaco region.

    Directory of Open Access Journals (Sweden)

    Natalia Capriotti

    Full Text Available BACKGROUND: Chagas' disease is an important public health concern in Latin America. Despite intensive vector control efforts using pyrethroid insecticides, the elimination of Triatoma infestans has failed in the Gran Chaco, an ecoregion that extends over Argentina, Paraguay, Bolivia and Brazil. The voltage-gated sodium channel is the target site of pyrethroid insecticides. Point mutations in domain II region of the channel have been implicated in pyrethroid resistance of several insect species. METHODS AND FINDINGS: In the present paper, we identify L925I, a new pyrethroid resistance-conferring mutation in T. infestans. This mutation has been found only in hemipterans. In T. infestans, L925I mutation occurs in a resistant population from the Gran Chaco region and is associated with inefficiency in the control campaigns. We also describe a method to detect L925I mutation in individuals from the field. CONCLUSIONS AND SIGNIFICANCE: The findings have important implications in the implementation of strategies for resistance management and in the rational design of campaigns for the control of Chagas' disease transmission.

  9. The calcite/water interface II. Effect of added lattice ions on the charge properties and adsorption of sodium polyacrylate.

    Science.gov (United States)

    Eriksson, Rasmus; Merta, Juha; Rosenholm, Jarl B

    2008-10-15

    The origin of the surface potential of calcium carbonate in aqueous dispersions and the dissolution of calcite in systems containing excess Ca(2+) and CO(3)(2-) have been the subjects of this study. In addition, stabilization of calcite particles with an anionic polyelectrolyte (sodium polyacrylate (NaPA)) and the effect on surface potential and dissolution of calcite have been studied. Preferential dissolution of either Ca(2+) or CO(3)(2-) from the surface, which is governed by the partial pressure of CO(2) in solution and the pH of the solution, mainly determines the surface potential. Both lattice ions (Ca(2+) and CO(3)(2-)) adsorb onto the surface and thus alter the surface potential. NaPA adsorbs strongly onto the calcite surface regardless of background electrolyte concentration, and reverses the surface potential to negative values. Chelation of the surface due to NaPA can be partly prevented by adding Ca(2+) to the dispersion. PMID:18675424

  10. Where is the spike generator of the cochlear nerve? Voltage-gated sodium channels in the mouse cochlea.

    OpenAIRE

    Hossain, Waheeda A.; Antic, Srdjan D.; Yang, Yang; Rasband, Matthew N; Morest, D. Kent

    2005-01-01

    The origin of the action potential in the cochlea has been a long-standing puzzle. Since voltage-dependent Na+ (Nav) channels are essential for action potential generation, we investigated the detailed distribution of Nav1.6 and Nav1.2 in the cochlear ganglion, cochlear nerve, and organ of Corti, including the Type I and Type II ganglion cells. In most Type I ganglion cells, Nav1.6 was present at the first nodes flanking the myelinated bipolar cell body and at subsequent nodes of Ranvier. In ...

  11. Electron Mobility Exceeding 10 cm(2) V(-1) s(-1) and Band-Like Charge Transport in Solution-Processed n-Channel Organic Thin-Film Transistors.

    Science.gov (United States)

    Xu, Xiaomin; Yao, Yifan; Shan, Bowen; Gu, Xiao; Liu, Danqing; Liu, Jinyu; Xu, Jianbin; Zhao, Ni; Hu, Wenping; Miao, Qian

    2016-07-01

    Solution-processed n-channel organic thin-film transistors (OTFTs) that exhibit a field-effect mobility as high as 11 cm(2) V(-1) s(-1) at room temperature and a band-like temperature dependence of electron mobility are reported. By comparison of solution-processed OTFTs with vacuum-deposited OTFTs of the same organic semiconductor, it is found that grain boundaries are a key factor inhibiting band-like charge transport. PMID:27151777

  12. The evaluations of the influence of surface conductivity to the energy of particles in discharge channel and interaction force in contact charging process

    Energy Technology Data Exchange (ETDEWEB)

    Alisoy, H.Z. [Department of Electric and Electronics Engineering, Inonu University, 44280 Malatya (Turkey)]. E-mail: halis@inonu.edu.tr; Alisoy, G.T. [Department of Mathematics Education, Inonu University, 44280 Malatya (Turkey); Sahin, A. [Department of Physics, Inonu University, 44280 Malatya (Turkey); Yeroglu, C. [Department of Electric and Electronics Engineering, Inonu University, 44280 Malatya (Turkey)

    2006-12-18

    In this Letter, we present some analytical expressions by using the equations of electric field, inside and outside of a cylindrical void, taking the surface conductivity into consideration. We apply the obtained expressions to the high voltage insulation and ion electron technology, such as: (i) energies of charged particles occurring in discharge channel in accordance with Townsend approach; (ii) interaction force between the dielectric particle and the electrode for DC and AC cases.

  13. Intracellular shunting of O2− contributes to charge compensation and preservation of neutrophil respiratory burst in the absence of voltage-gated proton channel activity

    International Nuclear Information System (INIS)

    Proton efflux via voltage-gated proton channels (Hv1) is considered to mediate the charge compensation necessary to preserve NADPH oxidase activity during the respiratory burst. Using the Hv1 inhibitor Zn2+, we found that the PMA-induced respiratory burst of human neutrophils is inhibited when assessed as extracellular production of O2− and H2O2, in accordance with literature studies, but, surprisingly, unaffected when measured as oxygen consumption or total (extracellular plus intracellular) H2O2 production. Furthermore, we show that inhibiting Hv1 with Zn2+ results in an increased production of intracellular ROS. Similar results, i.e. decreased extracellular and increased intracellular ROS production, were obtained using a human granulocyte-like cell line with severely impaired Hv1 expression. Acidic extracellular pH, which dampens proton efflux, also augmented intracellular production of H2O2. Zinc caused an increase in the rate but not in the extent of depolarization and cytosolic acidification indicating that mechanisms other than proton efflux take part in charge compensation. Our results suggest a hitherto unpredicted mechanism of charge compensation whereby, in the absence of proton efflux, part of O2− generated within gp91phox in the plasma membrane is shunted intracellularly down electrochemical gradient to dampen excessive depolarization. This would preserve NADPH oxidase activity under conditions such as the inflammatory exudate in which the acidic pH hinders charge compensation by proton efflux. Highlights: • Neutrophils’ respiratory burst is not inhibited by the H+ channel inhibitor Zn2+. • Intracellular production of O2− and H2O2 is increased in the presence of Zn2+. • Intracellular H2O2 production is increased in H+ channels knock-down cells. • Zn2+ increases the rate but not the extent of depolarization and pHi decrease. • Intracellular shunting of O2− contributes to charge compensation in neutrophils

  14. 电压门控钠离子通道与口面部疼痛的研究进展%The Progress of Research of Voltage-gated Sodium Channels and Orofacial Pain

    Institute of Scientific and Technical Information of China (English)

    朱凌

    2012-01-01

    The volt age-gated sodium channel is essential in the generation and conduction of action potentials. The biophysical properties of this ion channel can determine the response oi nociceptoi to noxious stimuli as well as the final level of pain. Sodium channels may affect the activation and inactivation of othej ion channels( such as the activation of potassium channels, calcium channels )to change the response of neurons to the stimuli,thus the sodium ion channels are potential targets for the treatment of neuropathic pain. Understanding the ion channel expression is of great importance to the control of neuional excitability as we! as the treatment of pain.%电压门控钠离子通道,在动作电位的产生和传导中至关重要,这种离子通道的生物物理性质决定伤害感受器对有害刺激的应答和最终经历的疼痛水平.钠离子通道可能会影响其他离子通道(如钾离子通道、钙离子通道)的激活和失活,改变神经元对刺激的应答,因而钠离子通道是用于治疗神经性疼痛的潜在目标.了解离子通道的表达对控制神经兴奋性、治疗疼痛具有重要意义.

  15. Development of two-channel prototype ITER vacuum ultraviolet spectrometer with back-illuminated charge-coupled device and microchannel plate detectors.

    Science.gov (United States)

    Seon, C R; Choi, S H; Cheon, M S; Pak, S; Lee, H G; Biel, W; Barnsley, R

    2010-10-01

    A vacuum ultraviolet (VUV) spectrometer of a five-channel spectral system is designed for ITER main plasma impurity measurement. To develop and verify the system design, a two-channel prototype system is fabricated with No. 3 (14.4-31.8 nm) and No. 4 (29.0-60.0 nm) among the five channels. The optical system consists of a collimating mirror to collect the light from source to slit, two holographic diffraction gratings with toroidal geometry, and two different electronic detectors. For the test of the prototype system, a hollow cathode lamp is used as a light source. To find the appropriate detector for ITER VUV system, two kinds of detectors of the back-illuminated charge-coupled device and the microchannel plate electron multiplier are tested, and their performance has been investigated.

  16. Development of two-channel prototype ITER vacuum ultraviolet spectrometer with back-illuminated charge-coupled device and microchannel plate detectors

    Energy Technology Data Exchange (ETDEWEB)

    Seon, C. R.; Choi, S. H.; Cheon, M. S.; Pak, S.; Lee, H. G. [National Fusion Research Institute, Gwahangno 113, Yuseong-gu, Daejeon 305-333 (Korea, Republic of); Biel, W. [Institut fuer Plasmaphysik, Forschungszentrum Juelich Gmbh, D-52425 Juelich (Germany); Barnsley, R. [ITER Organization, CS 90 046, 13067 St. Paul Lez Durance Cedex (France)

    2010-10-15

    A vacuum ultraviolet (VUV) spectrometer of a five-channel spectral system is designed for ITER main plasma impurity measurement. To develop and verify the system design, a two-channel prototype system is fabricated with No. 3 (14.4-31.8 nm) and No. 4 (29.0-60.0 nm) among the five channels. The optical system consists of a collimating mirror to collect the light from source to slit, two holographic diffraction gratings with toroidal geometry, and two different electronic detectors. For the test of the prototype system, a hollow cathode lamp is used as a light source. To find the appropriate detector for ITER VUV system, two kinds of detectors of the back-illuminated charge-coupled device and the microchannel plate electron multiplier are tested, and their performance has been investigated.

  17. Measurements of the $t\\bar{t}$ charge asymmetry using the dilepton decay channel in pp collisions at $\\sqrt{s}$=7 TeV

    CERN Document Server

    Chatrchyan, Serguei; Sirunyan, Albert M; Tumasyan, Armen; Adam, Wolfgang; Bergauer, Thomas; Dragicevic, Marko; Erö, Janos; Fabjan, Christian; Friedl, Markus; Fruehwirth, Rudolf; Ghete, Vasile Mihai; Hartl, Christian; Hörmann, Natascha; Hrubec, Josef; Jeitler, Manfred; Kiesenhofer, Wolfgang; Knünz, Valentin; Krammer, Manfred; Krätschmer, Ilse; Liko, Dietrich; Mikulec, Ivan; Rabady, Dinyar; Rahbaran, Babak; Rohringer, Herbert; Schöfbeck, Robert; Strauss, Josef; Taurok, Anton; Treberer-Treberspurg, Wolfgang; Waltenberger, Wolfgang; Wulz, Claudia-Elisabeth; Mossolov, Vladimir; Shumeiko, Nikolai; Suarez Gonzalez, Juan; Alderweireldt, Sara; Bansal, Monika; Bansal, Sunil; Cornelis, Tom; De Wolf, Eddi A; Janssen, Xavier; Knutsson, Albert; Luyckx, Sten; Mucibello, Luca; Ochesanu, Silvia; Roland, Benoit; Rougny, Romain; Van Haevermaet, Hans; Van Mechelen, Pierre; Van Remortel, Nick; Van Spilbeeck, Alex; Blekman, Freya; Blyweert, Stijn; D'Hondt, Jorgen; Heracleous, Natalie; Kalogeropoulos, Alexis; Keaveney, James; Kim, Tae Jeong; Lowette, Steven; Maes, Michael; Olbrechts, Annik; Strom, Derek; Tavernier, Stefaan; Van Doninck, Walter; Van Mulders, Petra; Van Onsem, Gerrit Patrick; Villella, Ilaria; Caillol, Cécile; Clerbaux, Barbara; De Lentdecker, Gilles; Favart, Laurent; Gay, Arnaud; Léonard, Alexandre; Marage, Pierre Edouard; Mohammadi, Abdollah; Perniè, Luca; Reis, Thomas; Seva, Tomislav; Thomas, Laurent; Vander Velde, Catherine; Vanlaer, Pascal; Wang, Jian; Adler, Volker; Beernaert, Kelly; Benucci, Leonardo; Cimmino, Anna; Costantini, Silvia; Crucy, Shannon; Dildick, Sven; Garcia, Guillaume; Klein, Benjamin; Lellouch, Jérémie; Mccartin, Joseph; Ocampo Rios, Alberto Andres; Ryckbosch, Dirk; Salva Diblen, Sinem; Sigamani, Michael; Strobbe, Nadja; Thyssen, Filip; Tytgat, Michael; Walsh, Sinead; Yazgan, Efe; Zaganidis, Nicolas; Basegmez, Suzan; Beluffi, Camille; Bruno, Giacomo; Castello, Roberto; Caudron, Adrien; Ceard, Ludivine; Da Silveira, Gustavo Gil; Delaere, Christophe; Du Pree, Tristan; Favart, Denis; Forthomme, Laurent; Giammanco, Andrea; Hollar, Jonathan; Jez, Pavel; Komm, Matthias; Lemaitre, Vincent; Liao, Junhui; Militaru, Otilia; Nuttens, Claude; Pagano, Davide; Pin, Arnaud; Piotrzkowski, Krzysztof; Popov, Andrey; Quertenmont, Loic; Selvaggi, Michele; Vidal Marono, Miguel; Vizan Garcia, Jesus Manuel; Beliy, Nikita; Caebergs, Thierry; Daubie, Evelyne; Hammad, Gregory Habib; Alves, Gilvan; Correa Martins Junior, Marcos; Dos Reis Martins, Thiago; Pol, Maria Elena; Henrique Gomes E Souza, Moacyr; Aldá Júnior, Walter Luiz; Carvalho, Wagner; Chinellato, Jose; Custódio, Analu; Da Costa, Eliza Melo; De Jesus Damiao, Dilson; De Oliveira Martins, Carley; Fonseca De Souza, Sandro; Malbouisson, Helena; Malek, Magdalena; Matos Figueiredo, Diego; Mundim, Luiz; Nogima, Helio; Prado Da Silva, Wanda Lucia; Santaolalla, Javier; Santoro, Alberto; Sznajder, Andre; Tonelli Manganote, Edmilson José; Vilela Pereira, Antonio; Bernardes, Cesar Augusto; De Almeida Dias, Flavia; Tomei, Thiago; De Moraes Gregores, Eduardo; Mercadante, Pedro G; Novaes, Sergio F; Padula, Sandra; Genchev, Vladimir; Iaydjiev, Plamen; Marinov, Andrey; Piperov, Stefan; Rodozov, Mircho; Sultanov, Georgi; Vutova, Mariana; Dimitrov, Anton; Glushkov, Ivan; Hadjiiska, Roumyana; Kozhuharov, Venelin; Litov, Leander; Pavlov, Borislav; Petkov, Peicho; Bian, Jian-Guo; Chen, Guo-Ming; Chen, He-Sheng; Chen, Mingshui; Du, Ran; Jiang, Chun-Hua; Liang, Dong; Liang, Song; Meng, Xiangwei; Plestina, Roko; Tao, Junquan; Wang, Xianyou; Wang, Zheng; Asawatangtrakuldee, Chayanit; Ban, Yong; Guo, Yifei; Li, Qiang; Li, Wenbo; Liu, Shuai; Mao, Yajun; Qian, Si-Jin; Wang, Dayong; Zhang, Linlin; Zou, Wei; Avila, Carlos; Carrillo Montoya, Camilo Andres; Chaparro Sierra, Luisa Fernanda; Florez, Carlos; Gomez, Juan Pablo; Gomez Moreno, Bernardo; Sanabria, Juan Carlos; Godinovic, Nikola; Lelas, Damir; Polic, Dunja; Puljak, Ivica; Antunovic, Zeljko; Kovac, Marko; Brigljevic, Vuko; Kadija, Kreso; Luetic, Jelena; Mekterovic, Darko; Morovic, Srecko; Sudic, Lucija; Attikis, Alexandros; Mavromanolakis, Georgios; Mousa, Jehad; Nicolaou, Charalambos; Ptochos, Fotios; Razis, Panos A; Finger, Miroslav; Finger Jr, Michael; Abdelalim, Ahmed Ali; Assran, Yasser; Elgammal, Sherif; Ellithi Kamel, Ali; Mahmoud, Mohammed; Radi, Amr; Kadastik, Mario; Müntel, Mait; Murumaa, Marion; Raidal, Martti; Rebane, Liis; Tiko, Andres; Eerola, Paula; Fedi, Giacomo; Voutilainen, Mikko; Härkönen, Jaakko; Karimäki, Veikko; Kinnunen, Ritva; Kortelainen, Matti J; Lampén, Tapio; Lassila-Perini, Kati; Lehti, Sami; Lindén, Tomas; Luukka, Panja-Riina; Mäenpää, Teppo; Peltola, Timo; Tuominen, Eija; Tuominiemi, Jorma; Tuovinen, Esa; Wendland, Lauri; Tuuva, Tuure; Besancon, Marc; Couderc, Fabrice; Dejardin, Marc; Denegri, Daniel; Fabbro, Bernard; Faure, Jean-Louis; Ferri, Federico; Ganjour, Serguei; Givernaud, Alain; Gras, Philippe; Hamel de Monchenault, Gautier; Jarry, Patrick; Locci, Elizabeth; Malcles, Julie; Nayak, Aruna; Rander, John; Rosowsky, André; Titov, Maksym; Baffioni, Stephanie; Beaudette, Florian; Busson, Philippe; Charlot, Claude; Daci, Nadir; Dahms, Torsten; Dalchenko, Mykhailo; Dobrzynski, Ludwik; Florent, Alice; Granier de Cassagnac, Raphael; Miné, Philippe; Mironov, Camelia; Naranjo, Ivo Nicolas; Nguyen, Matthew; Ochando, Christophe; Paganini, Pascal; Sabes, David; Salerno, Roberto; Sauvan, Jean-baptiste; Sirois, Yves; Veelken, Christian; Yilmaz, Yetkin; Zabi, Alexandre; Agram, Jean-Laurent; Andrea, Jeremy; Bloch, Daniel; Brom, Jean-Marie; Chabert, Eric Christian; Collard, Caroline; Conte, Eric; Drouhin, Frédéric; Fontaine, Jean-Charles; Gelé, Denis; Goerlach, Ulrich; Goetzmann, Christophe; Juillot, Pierre; Le Bihan, Anne-Catherine; Van Hove, Pierre; Gadrat, Sébastien; Beauceron, Stephanie; Beaupere, Nicolas; Boudoul, Gaelle; Brochet, Sébastien; Chasserat, Julien; Chierici, Roberto; Contardo, Didier; Depasse, Pierre; El Mamouni, Houmani; Fan, Jiawei; Fay, Jean; Gascon, Susan; Gouzevitch, Maxime; Ille, Bernard; Kurca, Tibor; Lethuillier, Morgan; Mirabito, Laurent; Perries, Stephane; Ruiz Alvarez, José David; Sgandurra, Louis; Sordini, Viola; Vander Donckt, Muriel; Verdier, Patrice; Viret, Sébastien; Xiao, Hong; Tsamalaidze, Zviad; Autermann, Christian; Beranek, Sarah; Bontenackels, Michael; Calpas, Betty; Edelhoff, Matthias; Feld, Lutz; Hindrichs, Otto; Klein, Katja; Ostapchuk, Andrey; Perieanu, Adrian; Raupach, Frank; Sammet, Jan; Schael, Stefan; Sprenger, Daniel; Weber, Hendrik; Wittmer, Bruno; Zhukov, Valery; Ata, Metin; Caudron, Julien; Dietz-Laursonn, Erik; Duchardt, Deborah; Erdmann, Martin; Fischer, Robert; Güth, Andreas; Hebbeker, Thomas; Heidemann, Carsten; Hoepfner, Kerstin; Klingebiel, Dennis; Knutzen, Simon; Kreuzer, Peter; Merschmeyer, Markus; Meyer, Arnd; Olschewski, Mark; Padeken, Klaas; Papacz, Paul; Reithler, Hans; Schmitz, Stefan Antonius; Sonnenschein, Lars; Teyssier, Daniel; Thüer, Sebastian; Weber, Martin; Cherepanov, Vladimir; Erdogan, Yusuf; Flügge, Günter; Geenen, Heiko; Geisler, Matthias; Haj Ahmad, Wael; Hoehle, Felix; Kargoll, Bastian; Kress, Thomas; Kuessel, Yvonne; Lingemann, Joschka; Nowack, Andreas; Nugent, Ian Michael; Perchalla, Lars; Pooth, Oliver; Stahl, Achim; Asin, Ivan; Bartosik, Nazar; Behr, Joerg; Behrenhoff, Wolf; Behrens, Ulf; Bell, Alan James; Bergholz, Matthias; Bethani, Agni; Borras, Kerstin; Burgmeier, Armin; Cakir, Altan; Calligaris, Luigi; Campbell, Alan; Choudhury, Somnath; Costanza, Francesco; Diez Pardos, Carmen; Dooling, Samantha; Dorland, Tyler; Eckerlin, Guenter; Eckstein, Doris; Eichhorn, Thomas; Flucke, Gero; Geiser, Achim; Grebenyuk, Anastasia; Gunnellini, Paolo; Habib, Shiraz; Hauk, Johannes; Hellwig, Gregor; Hempel, Maria; Horton, Dean; Jung, Hannes; Kasemann, Matthias; Katsas, Panagiotis; Kieseler, Jan; Kleinwort, Claus; Krämer, Mira; Krücker, Dirk; Lange, Wolfgang; Leonard, Jessica; Lipka, Katerina; Lohmann, Wolfgang; Lutz, Benjamin; Mankel, Rainer; Marfin, Ihar; Melzer-Pellmann, Isabell-Alissandra; Meyer, Andreas Bernhard; Mnich, Joachim; Mussgiller, Andreas; Naumann-Emme, Sebastian; Novgorodova, Olga; Nowak, Friederike; Ntomari, Eleni; Perrey, Hanno; Petrukhin, Alexey; Pitzl, Daniel; Placakyte, Ringaile; Raspereza, Alexei; Ribeiro Cipriano, Pedro M; Riedl, Caroline; Ron, Elias; Sahin, Mehmet Özgür; Salfeld-Nebgen, Jakob; Saxena, Pooja; Schmidt, Ringo; Schoerner-Sadenius, Thomas; Schröder, Matthias; Stein, Matthias; Vargas Trevino, Andrea Del Rocio; Walsh, Roberval; Wissing, Christoph; Aldaya Martin, Maria; Blobel, Volker; Enderle, Holger; Erfle, Joachim; Garutti, Erika; Goebel, Kristin; Görner, Martin; Gosselink, Martijn; Haller, Johannes; Höing, Rebekka Sophie; Kirschenmann, Henning; Klanner, Robert; Kogler, Roman; Lange, Jörn; Lapsien, Tobias; Lenz, Teresa; Marchesini, Ivan; Ott, Jochen; Peiffer, Thomas; Pietsch, Niklas; Rathjens, Denis; Sander, Christian; Schettler, Hannes; Schleper, Peter; Schlieckau, Eike; Schmidt, Alexander; Seidel, Markus; Sibille, Jennifer; Sola, Valentina; Stadie, Hartmut; Steinbrück, Georg; Troendle, Daniel; Usai, Emanuele; Vanelderen, Lukas; Barth, Christian; Baus, Colin; Berger, Joram; Böser, Christian; Butz, Erik; Chwalek, Thorsten; De Boer, Wim; Descroix, Alexis; Dierlamm, Alexander; Feindt, Michael; Guthoff, Moritz; Hartmann, Frank; Hauth, Thomas; Held, Hauke; Hoffmann, Karl-Heinz; Husemann, Ulrich; Katkov, Igor; Kornmayer, Andreas; Kuznetsova, Ekaterina; Lobelle Pardo, Patricia; Martschei, Daniel; Mozer, Matthias Ulrich; Müller, Thomas; Niegel, Martin; Nürnberg, Andreas; Oberst, Oliver; Quast, Gunter; Rabbertz, Klaus; Ratnikov, Fedor; Röcker, Steffen; Schilling, Frank-Peter; Schott, Gregory; Simonis, Hans-Jürgen; Stober, Fred-Markus Helmut; Ulrich, Ralf; Wagner-Kuhr, Jeannine; Wayand, Stefan; Weiler, Thomas; Wolf, Roger; Zeise, Manuel; Anagnostou, Georgios; Daskalakis, Georgios; Geralis, Theodoros; Kesisoglou, Stilianos; Kyriakis, Aristotelis; Loukas, Demetrios; Markou, Athanasios; Markou, Christos; Psallidas, Andreas; Topsis-Giotis, Iasonas; Gouskos, Loukas; Panagiotou, Apostolos; Saoulidou, Niki; Stiliaris, Efstathios; Aslanoglou, Xenofon; Evangelou, Ioannis; Flouris, Giannis; Foudas, Costas; Jones, John; Kokkas, Panagiotis; Manthos, Nikolaos; Papadopoulos, Ioannis; Paradas, Evangelos; Bencze, Gyorgy; Hajdu, Csaba; Hidas, Pàl; Horvath, Dezso; Sikler, Ferenc; Veszpremi, Viktor; Vesztergombi, Gyorgy; Zsigmond, Anna Julia; Beni, Noemi; Czellar, Sandor; Molnar, Jozsef; Palinkas, Jozsef; Szillasi, Zoltan; Karancsi, János; Raics, Peter; Trocsanyi, Zoltan Laszlo; Ujvari, Balazs; Swain, Sanjay Kumar; Beri, Suman Bala; Bhatnagar, Vipin; Dhingra, Nitish; Gupta, Ruchi; Kaur, Manjit; Mehta, Manuk Zubin; Mittal, Monika; Nishu, Nishu; Sharma, Archana; Singh, Jasbir; Kumar, Ashok; Kumar, Arun; Ahuja, Sudha; Bhardwaj, Ashutosh; Choudhary, Brajesh C; Kumar, Ajay; Malhotra, Shivali; Naimuddin, Md; Ranjan, Kirti; Sharma, Varun; Shivpuri, Ram Krishen; Banerjee, Sunanda; Bhattacharya, Satyaki; Chatterjee, Kalyanmoy; Dutta, Suchandra; Gomber, Bhawna; Jain, Sandhya; Jain, Shilpi; Khurana, Raman; Modak, Atanu; Mukherjee, Swagata; Roy, Debarati; Sarkar, Subir; Sharan, Manoj; Singh, Anil; Abdulsalam, Abdulla; Dutta, Dipanwita; Kailas, Swaminathan; Kumar, Vineet; Mohanty, Ajit Kumar; Pant, Lalit Mohan; Shukla, Prashant; Topkar, Anita; Aziz, Tariq; Chatterjee, Rajdeep Mohan; Ganguly, Sanmay; Ghosh, Saranya; Guchait, Monoranjan; Gurtu, Atul; Kole, Gouranga; Kumar, Sanjeev; Maity, Manas; Majumder, Gobinda; Mazumdar, Kajari; Mohanty, Gagan Bihari; Parida, Bibhuti; Sudhakar, Katta; Wickramage, Nadeesha; Banerjee, Sudeshna; Dugad, Shashikant; Arfaei, Hessamaddin; Bakhshiansohi, Hamed; Behnamian, Hadi; Etesami, Seyed Mohsen; Fahim, Ali; Jafari, Abideh; Khakzad, Mohsen; Mohammadi Najafabadi, Mojtaba; Naseri, Mohsen; Paktinat Mehdiabadi, Saeid; Safarzadeh, Batool; Zeinali, Maryam; Grunewald, Martin; Abbrescia, Marcello; Barbone, Lucia; Calabria, Cesare; Chhibra, Simranjit Singh; Colaleo, Anna; Creanza, Donato; De Filippis, Nicola; De Palma, Mauro; Fiore, Luigi; Iaselli, Giuseppe; Maggi, Giorgio; Maggi, Marcello; Marangelli, Bartolomeo; My, Salvatore; Nuzzo, Salvatore; Pacifico, Nicola; Pompili, Alexis; Pugliese, Gabriella; Radogna, Raffaella; Selvaggi, Giovanna; Silvestris, Lucia; Singh, Gurpreet; Venditti, Rosamaria; Verwilligen, Piet; Zito, Giuseppe; Abbiendi, Giovanni; Benvenuti, Alberto; Bonacorsi, Daniele; Braibant-Giacomelli, Sylvie; Brigliadori, Luca; Campanini, Renato; Capiluppi, Paolo; Castro, Andrea; Cavallo, Francesca Romana; Codispoti, Giuseppe; Cuffiani, Marco; Dallavalle, Gaetano-Marco; Fabbri, Fabrizio; Fanfani, Alessandra; Fasanella, Daniele; Giacomelli, Paolo; Grandi, Claudio; Guiducci, Luigi; Marcellini, Stefano; Masetti, Gianni; Meneghelli, Marco; Montanari, Alessandro; Navarria, Francesco; Odorici, Fabrizio; Perrotta, Andrea; Primavera, Federica; Rossi, Antonio; Rovelli, Tiziano; Siroli, Gian Piero; Tosi, Nicolò; Travaglini, Riccardo; Albergo, Sebastiano; Cappello, Gigi; Chiorboli, Massimiliano; Costa, Salvatore; Giordano, Ferdinando; Potenza, Renato; Tricomi, Alessia; Tuve, Cristina; Barbagli, Giuseppe; Ciulli, Vitaliano; Civinini, Carlo; D'Alessandro, Raffaello; Focardi, Ettore; Gallo, Elisabetta; Gonzi, Sandro; Gori, Valentina; Lenzi, Piergiulio; Meschini, Marco; Paoletti, Simone; Sguazzoni, Giacomo; Tropiano, Antonio; Benussi, Luigi; Bianco, Stefano; Fabbri, Franco; Piccolo, Davide; Fabbricatore, Pasquale; Ferretti, Roberta; Ferro, Fabrizio; Lo Vetere, Maurizio; Musenich, Riccardo; Robutti, Enrico; Tosi, Silvano; Dinardo, Mauro Emanuele; Fiorendi, Sara; Gennai, Simone; Gerosa, Raffaele; Ghezzi, Alessio; Govoni, Pietro; Lucchini, Marco Toliman; Malvezzi, Sandra; Manzoni, Riccardo Andrea; Martelli, Arabella; Marzocchi, Badder; Menasce, Dario; Moroni, Luigi; Paganoni, Marco; Pedrini, Daniele; Ragazzi, Stefano; Redaelli, Nicola; Tabarelli de Fatis, Tommaso; Buontempo, Salvatore; Cavallo, Nicola; Di Guida, Salvatore; Fabozzi, Francesco; Iorio, Alberto Orso Maria; Lista, Luca; Meola, Sabino; Merola, Mario; Paolucci, Pierluigi; Azzi, Patrizia; Bacchetta, Nicola; Bellato, Marco; Bisello, Dario; Branca, Antonio; Carlin, Roberto; Checchia, Paolo; Dorigo, Tommaso; Dosselli, Umberto; Galanti, Mario; Gasparini, Fabrizio; Gasparini, Ugo; Giubilato, Piero; Gozzelino, Andrea; Kanishchev, Konstantin; Lacaprara, Stefano; Lazzizzera, Ignazio; Margoni, Martino; Meneguzzo, Anna Teresa; Montecassiano, Fabio; Passaseo, Marina; Pazzini, Jacopo; Pozzobon, Nicola; Ronchese, Paolo; Simonetto, Franco; Torassa, Ezio; Tosi, Mia; Zotto, Pierluigi; Zucchetta, Alberto; Gabusi, Michele; Ratti, Sergio P; Riccardi, Cristina; Salvini, Paola; Vitulo, Paolo; Biasini, Maurizio; Bilei, Gian Mario; Fanò, Livio; Lariccia, Paolo; Mantovani, Giancarlo; Menichelli, Mauro; Romeo, Francesco; Saha, Anirban; Santocchia, Attilio; Spiezia, Aniello; Androsov, Konstantin; Azzurri, Paolo; Bagliesi, Giuseppe; Bernardini, Jacopo; Boccali, Tommaso; Broccolo, Giuseppe; Castaldi, Rino; Ciocci, Maria Agnese; Dell'Orso, Roberto; Fiori, Francesco; Foà, Lorenzo; Giassi, Alessandro; Grippo, Maria Teresa; Kraan, Aafke; Ligabue, Franco; Lomtadze, Teimuraz; Martini, Luca; Messineo, Alberto; Moon, Chang-Seong; Palla, Fabrizio; Rizzi, Andrea; Savoy-Navarro, Aurore; Serban, Alin Titus; Spagnolo, Paolo; Squillacioti, Paola; Tenchini, Roberto; Tonelli, Guido; Venturi, Andrea; Verdini, Piero Giorgio; Vernieri, Caterina; Barone, Luciano; Cavallari, Francesca; Del Re, Daniele; Diemoz, Marcella; Grassi, Marco; Jorda, Clara; Longo, Egidio; Margaroli, Fabrizio; Meridiani, Paolo; Micheli, Francesco; Nourbakhsh, Shervin; Organtini, Giovanni; Paramatti, Riccardo; Rahatlou, Shahram; Rovelli, Chiara; Soffi, Livia; Traczyk, Piotr; Amapane, Nicola; Arcidiacono, Roberta; Argiro, Stefano; Arneodo, Michele; Bellan, Riccardo; Biino, Cristina; Cartiglia, Nicolo; Casasso, Stefano; Costa, Marco; Degano, Alessandro; Demaria, Natale; Mariotti, Chiara; Maselli, Silvia; Migliore, Ernesto; Monaco, Vincenzo; Musich, Marco; Obertino, Maria Margherita; Ortona, Giacomo; Pacher, Luca; Pastrone, Nadia; Pelliccioni, Mario; Potenza, Alberto; Romero, Alessandra; Ruspa, Marta; Sacchi, Roberto; Solano, Ada; Staiano, Amedeo; Tamponi, Umberto; Belforte, Stefano; Candelise, Vieri; Casarsa, Massimo; Cossutti, Fabio; Della Ricca, Giuseppe; Gobbo, Benigno; La Licata, Chiara; Marone, Matteo; Montanino, Damiana; Penzo, Aldo; Schizzi, Andrea; Umer, Tomo; Zanetti, Anna; Chang, Sunghyun; Kim, Tae Yeon; Nam, Soon-Kwon; Kim, Dong Hee; Kim, Gui Nyun; Kim, Ji Eun; Kim, Min Suk; Kong, Dae Jung; Lee, Sangeun; Oh, Young Do; Park, Hyangkyu; Son, Dong-Chul; Kim, Jae Yool; Kim, Zero Jaeho; Song, Sanghyeon; Choi, Suyong; Gyun, Dooyeon; Hong, Byung-Sik; Jo, Mihee; Kim, Hyunchul; Kim, Yongsun; Lee, Kyong Sei; Park, Sung Keun; Roh, Youn; Choi, Minkyoo; Kim, Ji Hyun; Park, Chawon; Park, Inkyu; Park, Sangnam; Ryu, Geonmo; Choi, Young-Il; Choi, Young Kyu; Goh, Junghwan; Kwon, Eunhyang; Lee, Byounghoon; Lee, Jongseok; Seo, Hyunkwan; Yu, Intae; Juodagalvis, Andrius; Komaragiri, Jyothsna Rani; Castilla-Valdez, Heriberto; De La Cruz-Burelo, Eduard; Heredia-de La Cruz, Ivan; Lopez-Fernandez, Ricardo; Martínez-Ortega, Jorge; Sánchez Hernández, Alberto; Villasenor-Cendejas, Luis Manuel; Carrillo Moreno, Salvador; Vazquez Valencia, Fabiola; Salazar Ibarguen, Humberto Antonio; Casimiro Linares, Edgar; Morelos Pineda, Antonio; Krofcheck, David; Butler, Philip H; Doesburg, Robert; Reucroft, Steve; Ahmad, Ashfaq; Ahmad, Muhammad; Asghar, Muhammad Irfan; Butt, Jamila; Hassan, Qamar; Hoorani, Hafeez R; Khan, Wajid Ali; Khurshid, Taimoor; Qazi, Shamona; Shah, Mehar Ali; Shoaib, Muhammad; Bialkowska, Helena; Bluj, Michal; Boimska, Bożena; Frueboes, Tomasz; Górski, Maciej; Kazana, Malgorzata; Nawrocki, Krzysztof; Romanowska-Rybinska, Katarzyna; Szleper, Michal; Wrochna, Grzegorz; Zalewski, Piotr; Brona, Grzegorz; Bunkowski, Karol; Cwiok, Mikolaj; Dominik, Wojciech; Doroba, Krzysztof; Kalinowski, Artur; Konecki, Marcin; Krolikowski, Jan; Misiura, Maciej; Wolszczak, Weronika; Bargassa, Pedrame; Beirão Da Cruz E Silva, Cristóvão; Faccioli, Pietro; Ferreira Parracho, Pedro Guilherme; Gallinaro, Michele; Nguyen, Federico; Rodrigues Antunes, Joao; Seixas, Joao; Varela, Joao; Vischia, Pietro; Afanasiev, Serguei; Golutvin, Igor; Karjavin, Vladimir; Konoplyanikov, Viktor; Korenkov, Vladimir; Kozlov, Guennady; Lanev, Alexander; Malakhov, Alexander; Matveev, Viktor; Moisenz, Petr; Palichik, Vladimir; Perelygin, Victor; Shmatov, Sergey; Shulha, Siarhei; Skatchkov, Nikolai; Smirnov, Vitaly; Tikhonenko, Elena; Zarubin, Anatoli; Golovtsov, Victor; Ivanov, Yury; Kim, Victor; Levchenko, Petr; Murzin, Victor; Oreshkin, Vadim; Smirnov, Igor; Sulimov, Valentin; Uvarov, Lev; Vavilov, Sergey; Vorobyev, Alexey; Vorobyev, Andrey; Andreev, Yuri; Dermenev, Alexander; Gninenko, Sergei; Golubev, Nikolai; Kirsanov, Mikhail; Krasnikov, Nikolai; Pashenkov, Anatoli; Tlisov, Danila; Toropin, Alexander; Epshteyn, Vladimir; Gavrilov, Vladimir; Lychkovskaya, Natalia; Popov, Vladimir; Safronov, Grigory; Semenov, Sergey; Spiridonov, Alexander; Stolin, Viatcheslav; Vlasov, Evgueni; Zhokin, Alexander; Andreev, Vladimir; Azarkin, Maksim; Dremin, Igor; Kirakosyan, Martin; Leonidov, Andrey; Mesyats, Gennady; Rusakov, Sergey V; Vinogradov, Alexey; Belyaev, Andrey; Boos, Edouard; Bunichev, Viacheslav; Dubinin, Mikhail; Dudko, Lev; Ershov, Alexander; Gribushin, Andrey; Klyukhin, Vyacheslav; Lokhtin, Igor; Obraztsov, Stepan; Perfilov, Maxim; Savrin, Viktor; Tsirova, Natalia; Azhgirey, Igor; Bayshev, Igor; Bitioukov, Sergei; Kachanov, Vassili; Kalinin, Alexey; Konstantinov, Dmitri; Krychkine, Victor; Petrov, Vladimir; Ryutin, Roman; Sobol, Andrei; Tourtchanovitch, Leonid; Troshin, Sergey; Tyurin, Nikolay; Uzunian, Andrey; Volkov, Alexey; Adzic, Petar; Djordjevic, Milos; Ekmedzic, Marko; Milosevic, Jovan; Aguilar-Benitez, Manuel; Alcaraz Maestre, Juan; Battilana, Carlo; Calvo, Enrique; Cerrada, Marcos; Chamizo Llatas, Maria; Colino, Nicanor; De La Cruz, Begona; Delgado Peris, Antonio; Domínguez Vázquez, Daniel; Fernandez Bedoya, Cristina; Fernández Ramos, Juan Pablo; Ferrando, Antonio; Flix, Jose; Fouz, Maria Cruz; Garcia-Abia, Pablo; Gonzalez Lopez, Oscar; Goy Lopez, Silvia; Hernandez, Jose M; Josa, Maria Isabel; Merino, Gonzalo; Navarro De Martino, Eduardo; Pérez Calero Yzquierdo, Antonio María; Puerta Pelayo, Jesus; Quintario Olmeda, Adrián; Redondo, Ignacio; Romero, Luciano; Soares, Mara Senghi; Willmott, Carlos; Albajar, Carmen; de Trocóniz, Jorge F; Missiroli, Marino; Brun, Hugues; Cuevas, Javier; Fernandez Menendez, Javier; Folgueras, Santiago; Gonzalez Caballero, Isidro; Lloret Iglesias, Lara; Brochero Cifuentes, Javier Andres; Cabrillo, Iban Jose; Calderon, Alicia; Duarte Campderros, Jordi; Fernandez, Marcos; Gomez, Gervasio; Gonzalez Sanchez, Javier; Graziano, Alberto; Lopez Virto, Amparo; Marco, Jesus; Marco, Rafael; Martinez Rivero, Celso; Matorras, Francisco; Munoz Sanchez, Francisca Javiela; Piedra Gomez, Jonatan; Rodrigo, Teresa; Rodríguez-Marrero, Ana Yaiza; Ruiz-Jimeno, Alberto; Scodellaro, Luca; Vila, Ivan; Vilar Cortabitarte, Rocio; Abbaneo, Duccio; Auffray, Etiennette; Auzinger, Georg; Bachtis, Michail; Baillon, Paul; Ball, Austin; Barney, David; Benaglia, Andrea; Bendavid, Joshua; Benhabib, Lamia; Benitez, Jose F; Bernet, Colin; Bianchi, Giovanni; Bloch, Philippe; Bocci, Andrea; Bonato, Alessio; Bondu, Olivier; Botta, Cristina; Breuker, Horst; Camporesi, Tiziano; Cerminara, Gianluca; Christiansen, Tim; Coarasa Perez, Jose Antonio; Colafranceschi, Stefano; D'Alfonso, Mariarosaria; D'Enterria, David; Dabrowski, Anne; David Tinoco Mendes, Andre; De Guio, Federico; De Roeck, Albert; De Visscher, Simon; Dobson, Marc; Dupont-Sagorin, Niels; Elliott-Peisert, Anna; Eugster, Jürg; Franzoni, Giovanni; Funk, Wolfgang; Giffels, Manuel; Gigi, Dominique; Gill, Karl; Giordano, Domenico; Girone, Maria; Giunta, Marina; Glege, Frank; Gomez-Reino Garrido, Robert; Gowdy, Stephen; Guida, Roberto; Hammer, Josef; Hansen, Magnus; Harris, Philip; Innocente, Vincenzo; Janot, Patrick; Karavakis, Edward; Kousouris, Konstantinos; Krajczar, Krisztian; Lecoq, Paul; Lourenco, Carlos; Magini, Nicolo; Malgeri, Luca; Mannelli, Marcello; Masetti, Lorenzo; Meijers, Frans; Mersi, Stefano; Meschi, Emilio; Moortgat, Filip; Mulders, Martijn; Musella, Pasquale; Orsini, Luciano; Palencia Cortezon, Enrique; Perez, Emmanuelle; Perrozzi, Luca; Petrilli, Achille; Petrucciani, Giovanni; Pfeiffer, Andreas; Pierini, Maurizio; Pimiä, Martti; Piparo, Danilo; Plagge, Michael; Racz, Attila; Reece, William; Rolandi, Gigi; Rovere, Marco; Sakulin, Hannes; Santanastasio, Francesco; Schäfer, Christoph; Schwick, Christoph; Sekmen, Sezen; Sharma, Archana; Siegrist, Patrice; Silva, Pedro; Simon, Michal; Sphicas, Paraskevas; Spiga, Daniele; Steggemann, Jan; Stieger, Benjamin; Stoye, Markus; Tsirou, Andromachi; Veres, Gabor Istvan; Vlimant, Jean-Roch; Wöhri, Hermine Katharina; Zeuner, Wolfram Dietrich; Bertl, Willi; Deiters, Konrad; Erdmann, Wolfram; Horisberger, Roland; Ingram, Quentin; Kaestli, Hans-Christian; König, Stefan; Kotlinski, Danek; Langenegger, Urs; Renker, Dieter; Rohe, Tilman; Bachmair, Felix; Bäni, Lukas; Bianchini, Lorenzo; Bortignon, Pierluigi; Buchmann, Marco-Andrea; Casal, Bruno; Chanon, Nicolas; Deisher, Amanda; Dissertori, Günther; Dittmar, Michael; Donegà, Mauro; Dünser, Marc; Eller, Philipp; Grab, Christoph; Hits, Dmitry; Lustermann, Werner; Mangano, Boris; Marini, Andrea Carlo; Martinez Ruiz del Arbol, Pablo; Meister, Daniel; Mohr, Niklas; Nägeli, Christoph; Nef, Pascal; Nessi-Tedaldi, Francesca; Pandolfi, Francesco; Pape, Luc; Pauss, Felicitas; Peruzzi, Marco; Quittnat, Milena; Ronga, Frederic Jean; Rossini, Marco; Starodumov, Andrei; Takahashi, Maiko; Tauscher, Ludwig; Theofilatos, Konstantinos; Treille, Daniel; Wallny, Rainer; Weber, Hannsjoerg Artur; Amsler, Claude; Canelli, Maria Florencia; Chiochia, Vincenzo; De Cosa, Annapaola; Favaro, Carlotta; Hinzmann, Andreas; Hreus, Tomas; Ivova Rikova, Mirena; Kilminster, Benjamin; Millan Mejias, Barbara; Ngadiuba, Jennifer; Robmann, Peter; Snoek, Hella; Taroni, Silvia; Verzetti, Mauro; Yang, Yong; Cardaci, Marco; Chen, Kuan-Hsin; Ferro, Cristina; Kuo, Chia-Ming; Li, Syue-Wei; Lin, Willis; Lu, Yun-Ju; Volpe, Roberta; Yu, Shin-Shan; Bartalini, Paolo; Chang, Paoti; Chang, You-Hao; Chang, Yu-Wei; Chao, Yuan; Chen, Kai-Feng; Chen, Po-Hsun; Dietz, Charles; Grundler, Ulysses; Hou, George Wei-Shu; Hsiung, Yee; Kao, Kai-Yi; Lei, Yeong-Jyi; Liu, Yueh-Feng; Lu, Rong-Shyang; Majumder, Devdatta; Petrakou, Eleni; Shi, Xin; Shiu, Jing-Ge; Tzeng, Yeng-Ming; Wang, Minzu; Wilken, Rachel; Asavapibhop, Burin; Suwonjandee, Narumon; Adiguzel, Aytul; Bakirci, Mustafa Numan; Cerci, Salim; Dozen, Candan; Dumanoglu, Isa; Eskut, Eda; Girgis, Semiray; Gokbulut, Gul; Gurpinar, Emine; Hos, Ilknur; Kangal, Evrim Ersin; Kayis Topaksu, Aysel; Onengut, Gulsen; Ozdemir, Kadri; Ozturk, Sertac; Polatoz, Ayse; Sogut, Kenan; Sunar Cerci, Deniz; Tali, Bayram; Topakli, Huseyin; Vergili, Mehmet; Akin, Ilina Vasileva; Aliev, Takhmasib; Bilin, Bugra; Bilmis, Selcuk; Deniz, Muhammed; Gamsizkan, Halil; Guler, Ali Murat; Karapinar, Guler; Ocalan, Kadir; Ozpineci, Altug; Serin, Meltem; Sever, Ramazan; Surat, Ugur Emrah; Yalvac, Metin; Zeyrek, Mehmet; Gülmez, Erhan; Isildak, Bora; Kaya, Mithat; Kaya, Ozlem; Ozkorucuklu, Suat; Bahtiyar, Hüseyin; Barlas, Esra; Cankocak, Kerem; Günaydin, Yusuf Oguzhan; Vardarli, Fuat Ilkehan; Yücel, Mete; Levchuk, Leonid; Sorokin, Pavel; Brooke, James John; Clement, Emyr; Cussans, David; Flacher, Henning; Frazier, Robert; Goldstein, Joel; Grimes, Mark; Heath, Greg P; Heath, Helen F; Jacob, Jeson; Kreczko, Lukasz; Lucas, Chris; Meng, Zhaoxia; Newbold, Dave M; Paramesvaran, Sudarshan; Poll, Anthony; Senkin, Sergey; Smith, Vincent J; Williams, Thomas; Bell, Ken W; Belyaev, Alexander; Brew, Christopher; Brown, Robert M; Cockerill, David JA; Coughlan, John A; Harder, Kristian; Harper, Sam; Ilic, Jelena; Olaiya, Emmanuel; Petyt, David; Shepherd-Themistocleous, Claire; Thea, Alessandro; Tomalin, Ian R; Womersley, William John; Worm, Steven; Baber, Mark; Bainbridge, Robert; Buchmuller, Oliver; Burton, Darren; Colling, David; Cripps, Nicholas; Cutajar, Michael; Dauncey, Paul; Davies, Gavin; Della Negra, Michel; Ferguson, William; Fulcher, Jonathan; Futyan, David; Gilbert, Andrew; Guneratne Bryer, Arlo; Hall, Geoffrey; Hatherell, Zoe; Hays, Jonathan; Iles, Gregory; Jarvis, Martyn; Karapostoli, Georgia; Kenzie, Matthew; Lane, Rebecca; Lucas, Robyn; Lyons, Louis; Magnan, Anne-Marie; Marrouche, Jad; Mathias, Bryn; Nandi, Robin; Nash, Jordan; Nikitenko, Alexander; Pela, Joao; Pesaresi, Mark; Petridis, Konstantinos; Pioppi, Michele; Raymond, David Mark; Rogerson, Samuel; Rose, Andrew; Seez, Christopher; Sharp, Peter; Sparrow, Alex; Tapper, Alexander; Vazquez Acosta, Monica; Virdee, Tejinder; Wakefield, Stuart; Wardle, Nicholas; Cole, Joanne; Hobson, Peter R; Khan, Akram; Kyberd, Paul; Leggat, Duncan; Leslie, Dawn; Martin, William; Reid, Ivan; Symonds, Philip; Teodorescu, Liliana; Turner, Mark; Dittmann, Jay; Hatakeyama, Kenichi; Kasmi, Azeddine; Liu, Hongxuan; Scarborough, Tara; Charaf, Otman; Cooper, Seth; Henderson, Conor; Rumerio, Paolo; Avetisyan, Aram; Bose, Tulika; Fantasia, Cory; Heister, Arno; Lawson, Philip; Lazic, Dragoslav; Richardson, Clint; Rohlf, James; Sperka, David; St John, Jason; Sulak, Lawrence; Alimena, Juliette; Bhattacharya, Saptaparna; Christopher, Grant; Cutts, David; Demiragli, Zeynep; Ferapontov, Alexey; Garabedian, Alex; Heintz, Ulrich; Jabeen, Shabnam; Kukartsev, Gennadiy; Laird, Edward; Landsberg, Greg; Luk, Michael; Narain, Meenakshi; Segala, Michael; Sinthuprasith, Tutanon; Speer, Thomas; Swanson, Joshua; Breedon, Richard; Breto, Guillermo; Calderon De La Barca Sanchez, Manuel; Chauhan, Sushil; Chertok, Maxwell; Conway, John; Conway, Rylan; Cox, Peter Timothy; Erbacher, Robin; Gardner, Michael; Ko, Winston; Kopecky, Alexandra; Lander, Richard; Miceli, Tia; Mulhearn, Michael; Pellett, Dave; Pilot, Justin; Ricci-Tam, Francesca; Rutherford, Britney; Searle, Matthew; Shalhout, Shalhout; Smith, John; Squires, Michael; Tripathi, Mani; Wilbur, Scott; Yohay, Rachel; Andreev, Valeri; Cline, David; Cousins, Robert; Erhan, Samim; Everaerts, Pieter; Farrell, Chris; Felcini, Marta; Hauser, Jay; Ignatenko, Mikhail; Jarvis, Chad; Rakness, Gregory; Schlein, Peter; Takasugi, Eric; Valuev, Vyacheslav; Weber, Matthias; Babb, John; Clare, Robert; Ellison, John Anthony; Gary, J William; Hanson, Gail; Heilman, Jesse; Jandir, Pawandeep; Lacroix, Florent; Liu, Hongliang; Long, Owen Rosser; Luthra, Arun; Malberti, Martina; Nguyen, Harold; Shrinivas, Amithabh; Sturdy, Jared; Sumowidagdo, Suharyo; Wimpenny, Stephen; Andrews, Warren; Branson, James G; Cerati, Giuseppe Benedetto; Cittolin, Sergio; D'Agnolo, Raffaele Tito; Evans, David; Holzner, André; Kelley, Ryan; Klein, Daniel; Kovalskyi, Dmytro; Lebourgeois, Matthew; Letts, James; Macneill, Ian; Padhi, Sanjay; Palmer, Christopher; Pieri, Marco; Sani, Matteo; Sharma, Vivek; Simon, Sean; Sudano, Elizabeth; Tadel, Matevz; Tu, Yanjun; Vartak, Adish; Wasserbaech, Steven; Würthwein, Frank; Yagil, Avraham; Yoo, Jaehyeok; Barge, Derek; Bradmiller-Feld, John; Campagnari, Claudio; Danielson, Thomas; Dishaw, Adam; Flowers, Kristen; Franco Sevilla, Manuel; Geffert, Paul; George, Christopher; Golf, Frank; Incandela, Joe; Justus, Christopher; Magaña Villalba, Ricardo; Mccoll, Nickolas; Pavlunin, Viktor; Richman, Jeffrey; Rossin, Roberto; Stuart, David; To, Wing; West, Christopher; Apresyan, Artur; Bornheim, Adolf; Bunn, Julian; Chen, Yi; Di Marco, Emanuele; Duarte, Javier; Kcira, Dorian; Mott, Alexander; Newman, Harvey B; Pena, Cristian; Rogan, Christopher; Spiropulu, Maria; Timciuc, Vladlen; Wilkinson, Richard; Xie, Si; Zhu, Ren-Yuan; Azzolini, Virginia; Calamba, Aristotle; Carroll, Ryan; Ferguson, Thomas; Iiyama, Yutaro; Jang, Dong Wook; Paulini, Manfred; Russ, James; Vogel, Helmut; Vorobiev, Igor; Cumalat, John Perry; Drell, Brian Robert; Ford, William T; Gaz, Alessandro; Luiggi Lopez, Eduardo; Nauenberg, Uriel; Smith, James; Stenson, Kevin; Ulmer, Keith; Wagner, Stephen Robert; Alexander, James; Chatterjee, Avishek; Eggert, Nicholas; Gibbons, Lawrence Kent; Hopkins, Walter; Khukhunaishvili, Aleko; Kreis, Benjamin; Mirman, Nathan; Nicolas Kaufman, Gala; Patterson, Juliet Ritchie; Ryd, Anders; Salvati, Emmanuele; Sun, Werner; Teo, Wee Don; Thom, Julia; Thompson, Joshua; Tucker, Jordan; Weng, Yao; Winstrom, Lucas; Wittich, Peter; Winn, Dave; Abdullin, Salavat; Albrow, Michael; Anderson, Jacob; Apollinari, Giorgio; Bauerdick, Lothar AT; Beretvas, Andrew; Berryhill, Jeffrey; Bhat, Pushpalatha C; Burkett, Kevin; Butler, Joel Nathan; Chetluru, Vasundhara; Cheung, Harry; Chlebana, Frank; Cihangir, Selcuk; Elvira, Victor Daniel; Fisk, Ian; Freeman, Jim; Gao, Yanyan; Gottschalk, Erik; Gray, Lindsey; Green, Dan; Grünendahl, Stefan; Gutsche, Oliver; Hare, Daryl; Harris, Robert M; Hirschauer, James; Hooberman, Benjamin; Jindariani, Sergo; Johnson, Marvin; Joshi, Umesh; Kaadze, Ketino; Klima, Boaz; Kwan, Simon; Linacre, Jacob; Lincoln, Don; Lipton, Ron; Lykken, Joseph; Maeshima, Kaori; Marraffino, John Michael; Martinez Outschoorn, Verena Ingrid; Maruyama, Sho; Mason, David; McBride, Patricia; Mishra, Kalanand; Mrenna, Stephen; Musienko, Yuri; Nahn, Steve; Newman-Holmes, Catherine; O'Dell, Vivian; Prokofyev, Oleg; Ratnikova, Natalia; Sexton-Kennedy, Elizabeth; Sharma, Seema; Spalding, William J; Spiegel, Leonard; Taylor, Lucas; Tkaczyk, Slawek; Tran, Nhan Viet; Uplegger, Lorenzo; Vaandering, Eric Wayne; Vidal, Richard; Whitbeck, Andrew; Whitmore, Juliana; Wu, Weimin; Yang, Fan; Yun, Jae Chul; Acosta, Darin; Avery, Paul; Bourilkov, Dimitri; Cheng, Tongguang; Das, Souvik; De Gruttola, Michele; Di Giovanni, Gian Piero; Dobur, Didar; Field, Richard D; Fisher, Matthew; Fu, Yu; Furic, Ivan-Kresimir; Hugon, Justin; Kim, Bockjoo; Konigsberg, Jacobo; Korytov, Andrey; Kropivnitskaya, Anna; Kypreos, Theodore; Low, Jia Fu; Matchev, Konstantin; Milenovic, Predrag; Mitselmakher, Guenakh; Muniz, Lana; Rinkevicius, Aurelijus; Shchutska, Lesya; Skhirtladze, Nikoloz; Snowball, Matthew; Yelton, John; Zakaria, Mohammed; Gaultney, Vanessa; Hewamanage, Samantha; Linn, Stephan; Markowitz, Pete; Martinez, German; Rodriguez, Jorge Luis; Adams, Todd; Askew, Andrew; Bochenek, Joseph; Chen, Jie; Diamond, Brendan; Haas, Jeff; Hagopian, Sharon; Hagopian, Vasken; Johnson, Kurtis F; Prosper, Harrison; Veeraraghavan, Venkatesh; Weinberg, Marc; Baarmand, Marc M; Dorney, Brian; Hohlmann, Marcus; Kalakhety, Himali; Yumiceva, Francisco; Adams, Mark Raymond; Apanasevich, Leonard; Bazterra, Victor Eduardo; Betts, Russell Richard; Bucinskaite, Inga; Cavanaugh, Richard; Evdokimov, Olga; Gauthier, Lucie; Gerber, Cecilia Elena; Hofman, David Jonathan; Khalatyan, Samvel; Kurt, Pelin; Moon, Dong Ho; O'Brien, Christine; Silkworth, Christopher; Turner, Paul; Varelas, Nikos; Akgun, Ugur; Albayrak, Elif Asli; Bilki, Burak; Clarida, Warren; Dilsiz, Kamuran; Duru, Firdevs; Haytmyradov, Maksat; Merlo, Jean-Pierre; Mermerkaya, Hamit; Mestvirishvili, Alexi; Moeller, Anthony; Nachtman, Jane; Ogul, Hasan; Onel, Yasar; Ozok, Ferhat; Rahmat, Rahmat; Sen, Sercan; Tan, Ping; Tiras, Emrah; Wetzel, James; Yetkin, Taylan; Yi, Kai; Barnett, Bruce Arnold; Blumenfeld, Barry; Bolognesi, Sara; Fehling, David; Gritsan, Andrei; Maksimovic, Petar; Martin, Christopher; Swartz, Morris; Baringer, Philip; Bean, Alice; Benelli, Gabriele; Kenny III, Raymond Patrick; Murray, Michael; Noonan, Daniel; Sanders, Stephen; Sekaric, Jadranka; Stringer, Robert; Wang, Quan; Wood, Jeffrey Scott; Barfuss, Anne-Fleur; Chakaberia, Irakli; Ivanov, Andrew; Khalil, Sadia; Makouski, Mikhail; Maravin, Yurii; Saini, Lovedeep Kaur; Shrestha, Shruti; Svintradze, Irakli; Gronberg, Jeffrey; Lange, David; Rebassoo, Finn; Wright, Douglas; Baden, Drew; Calvert, Brian; Eno, Sarah Catherine; Gomez, Jaime; Hadley, Nicholas John; Kellogg, Richard G; Kolberg, Ted; Lu, Ying; Marionneau, Matthieu; Mignerey, Alice; Pedro, Kevin; Skuja, Andris; Temple, Jeffrey; Tonjes, Marguerite; Tonwar, Suresh C; Apyan, Aram; Barbieri, Richard; Bauer, Gerry; Busza, Wit; Cali, Ivan Amos; Chan, Matthew; Di Matteo, Leonardo; Dutta, Valentina; Gomez Ceballos, Guillelmo; Goncharov, Maxim; Gulhan, Doga; Klute, Markus; Lai, Yue Shi; Lee, Yen-Jie; Levin, Andrew; Luckey, Paul David; Ma, Teng; Paus, Christoph; Ralph, Duncan; Roland, Christof; Roland, Gunther; Stephans, George; Stöckli, Fabian; Sumorok, Konstanty; Velicanu, Dragos; Veverka, Jan; Wyslouch, Bolek; Yang, Mingming; Yoon, Sungho; Zanetti, Marco; Zhukova, Victoria; Dahmes, Bryan; De Benedetti, Abraham; Gude, Alexander; Kao, Shih-Chuan; Klapoetke, Kevin; Kubota, Yuichi; Mans, Jeremy; Pastika, Nathaniel; Rusack, Roger; Singovsky, Alexander; Tambe, Norbert; Turkewitz, Jared; Acosta, John Gabriel; Cremaldi, Lucien Marcus; Kroeger, Rob; Oliveros, Sandra; Perera, Lalith; Sanders, David A; Summers, Don; Avdeeva, Ekaterina; Bloom, Kenneth; Bose, Suvadeep; Claes, Daniel R; Dominguez, Aaron; Gonzalez Suarez, Rebeca; Keller, Jason; Knowlton, Dan; Kravchenko, Ilya; Lazo-Flores, Jose; Malik, Sudhir; Meier, Frank; Snow, Gregory R; Dolen, James; Godshalk, Andrew; Iashvili, Ia; Jain, Supriya; Kharchilava, Avto; Kumar, Ashish; Rappoccio, Salvatore; Alverson, George; Barberis, Emanuela; Baumgartel, Darin; Chasco, Matthew; Haley, Joseph; Massironi, Andrea; Nash, David; Orimoto, Toyoko; Trocino, Daniele; Wood, Darien; Zhang, Jinzhong; Anastassov, Anton; Hahn, Kristan Allan; Kubik, Andrew; Lusito, Letizia; Mucia, Nicholas; Odell, Nathaniel; Pollack, Brian; Pozdnyakov, Andrey; Schmitt, Michael; Stoynev, Stoyan; Sung, Kevin; Velasco, Mayda; Won, Steven; Berry, Douglas; Brinkerhoff, Andrew; Chan, Kwok Ming; Drozdetskiy, Alexey; Hildreth, Michael; Jessop, Colin; Karmgard, Daniel John; Kellams, Nathan; Kolb, Jeff; Lannon, Kevin; Luo, Wuming; Lynch, Sean; Marinelli, Nancy; Morse, David Michael; Pearson, Tessa; Planer, Michael; Ruchti, Randy; Slaunwhite, Jason; Valls, Nil; Wayne, Mitchell; Wolf, Matthias; Woodard, Anna; Antonelli, Louis; Bylsma, Ben; Durkin, Lloyd Stanley; Flowers, Sean; Hill, Christopher; Hughes, Richard; Kotov, Khristian; Ling, Ta-Yung; Puigh, Darren; Rodenburg, Marissa; Smith, Geoffrey; Vuosalo, Carl; Winer, Brian L; Wolfe, Homer; Wulsin, Howard Wells; Berry, Edmund; Elmer, Peter; Halyo, Valerie; Hebda, Philip; Hegeman, Jeroen; Hunt, Adam; Jindal, Pratima; Koay, Sue Ann; Lujan, Paul; Marlow, Daniel; Medvedeva, Tatiana; Mooney, Michael; Olsen, James; Piroué, Pierre; Quan, Xiaohang; Raval, Amita; Saka, Halil; Stickland, David; Tully, Christopher; Werner, Jeremy Scott; Zenz, Seth Conrad; Zuranski, Andrzej; Brownson, Eric; Lopez, Angel; Mendez, Hector; Ramirez Vargas, Juan Eduardo; Alagoz, Enver; Benedetti, Daniele; Bolla, Gino; Bortoletto, Daniela; De Mattia, Marco; Everett, Adam; Hu, Zhen; Jha, Manoj; Jones, Matthew; Jung, Kurt; Kress, Matthew; Leonardo, Nuno; Lopes Pegna, David; Maroussov, Vassili; Merkel, Petra; Miller, David Harry; Neumeister, Norbert; Radburn-Smith, Benjamin Charles; Shipsey, Ian; Silvers, David; Svyatkovskiy, Alexey; Wang, Fuqiang; Xie, Wei; Xu, Lingshan; Yoo, Hwi Dong; Zablocki, Jakub; Zheng, Yu; Parashar, Neeti; Adair, Antony; Akgun, Bora; Ecklund, Karl Matthew; Geurts, Frank JM; Li, Wei; Michlin, Benjamin; Padley, Brian Paul; Redjimi, Radia; Roberts, Jay; Zabel, James; Betchart, Burton; Bodek, Arie; Covarelli, Roberto; de Barbaro, Pawel; Demina, Regina; Eshaq, Yossof; Ferbel, Thomas; Garcia-Bellido, Aran; Goldenzweig, Pablo; Han, Jiyeon; Harel, Amnon; Miner, Daniel Carl; Petrillo, Gianluca; Vishnevskiy, Dmitry; Zielinski, Marek; Bhatti, Anwar; Ciesielski, Robert; Demortier, Luc; Goulianos, Konstantin; Lungu, Gheorghe; Malik, Sarah; Mesropian, Christina; Arora, Sanjay; Barker, Anthony; Chou, John Paul; Contreras-Campana, Christian; Contreras-Campana, Emmanuel; Duggan, Daniel; Ferencek, Dinko; Gershtein, Yuri; Gray, Richard; Halkiadakis, Eva; Hidas, Dean; Lath, Amitabh; Panwalkar, Shruti; Park, Michael; Patel, Rishi; Rekovic, Vladimir; Robles, Jorge; Salur, Sevil; Schnetzer, Steve; Seitz, Claudia; Somalwar, Sunil; Stone, Robert; Thomas, Scott; Thomassen, Peter; Walker, Matthew; Rose, Keith; Spanier, Stefan; Yang, Zong-Chang; York, Andrew; Bouhali, Othmane; Eusebi, Ricardo; Flanagan, Will; Gilmore, Jason; Kamon, Teruki; Khotilovich, Vadim; Krutelyov, Vyacheslav; Montalvo, Roy; Osipenkov, Ilya; Pakhotin, Yuriy; Perloff, Alexx; Roe, Jeffrey; Safonov, Alexei; Sakuma, Tai; Suarez, Indara; Tatarinov, Aysen; Toback, David; Akchurin, Nural; Cowden, Christopher; Damgov, Jordan; Dragoiu, Cosmin; Dudero, Phillip Russell; Faulkner, James; Kovitanggoon, Kittikul; Kunori, Shuichi; Lee, Sung Won; Libeiro, Terence; Volobouev, Igor; Appelt, Eric; Delannoy, Andrés G; Greene, Senta; Gurrola, Alfredo; Johns, Willard; Maguire, Charles; Mao, Yaxian; Melo, Andrew; Sharma, Monika; Sheldon, Paul; Snook, Benjamin; Tuo, Shengquan; Velkovska, Julia; Arenton, Michael Wayne; Boutle, Sarah; Cox, Bradley; Francis, Brian; Goodell, Joseph; Hirosky, Robert; Ledovskoy, Alexander; Lin, Chuanzhe; Neu, Christopher; Wood, John; Gollapinni, Sowjanya; Harr, Robert; Karchin, Paul Edmund; Kottachchi Kankanamge Don, Chamath; Lamichhane, Pramod; Belknap, Donald; Borrello, Laura; Carlsmith, Duncan; Cepeda, Maria; Dasu, Sridhara; Duric, Senka; Friis, Evan; Grothe, Monika; Hall-Wilton, Richard; Herndon, Matthew; Hervé, Alain; Klabbers, Pamela; Klukas, Jeffrey; Lanaro, Armando; Levine, Aaron; Loveless, Richard; Mohapatra, Ajit; Ojalvo, Isabel; Perry, Thomas; Pierro, Giuseppe Antonio; Polese, Giovanni; Ross, Ian; Sakharov, Alexandre; Sarangi, Tapas; Savin, Alexander; Smith, Wesley H; Woods, Nathaniel

    2014-01-01

    The $t\\bar{t}$ charge asymmetry in proton-proton collisions at $\\sqrt{s}$=7 TeV is measured using the dilepton decay channel ($ee, e\\mu,$ or $\\mu\\mu$). The data correspond to a total integrated luminosity of 5.0 inverse-femtobarns, collected by the CMS experiment at the LHC. The top-antitop and lepton charge asymmetries, defined as the differences in absolute values of the rapidities between the reconstructed top quarks and antiquarks and of the pseudorapidities between the positive and negative leptons, respectively, are measured to be $A_C$ = -0.010 +/- 0.017 (stat.) +/- 0.008 (syst.) and $A_C^{lep}$ = 0.009 +/- 0.010 (stat.) +/- 0.006 (syst.). The lepton charge asymmetry is also measured as a function of the invariant mass, rapidity, and transverse momentum of the top-antitop system. All measurements are consistent with the expectations of the standard model.

  18. A 16-Channel high-resolution time and charge measurement module for the external target experiment in the CSR of HIRFL

    International Nuclear Information System (INIS)

    High precision time measurement is required in the readout of the neutron wall and TOF walls in the external target experiment of the Cooling Storage Ring (CSR) project in the Heavy Ion Research Facility in Lanzhou (HIRFL). Considering the time walk correction, both time and charge are measured in the readout electronics. In this 16-channel measurement module, time and charge information are digitized by TDCs at the same time based on the Time-Over-Threshold (TOT) method; meanwhile, by employing high-density ASIC chips, the electronics complexity is effectively reduced. Test results indicate that this module achieves a time resolution better than 25 ps and a charge resolution better than 5% over the input amplitude range from 50 mV to 3 V. (authors)

  19. Sodium-23 MRI of whole spine at 3 Tesla using a 5-channel receive-only phased-array and a whole-body transmit resonator

    Energy Technology Data Exchange (ETDEWEB)

    Malzacher, Matthias; Kalayciyan, Raffi; Konstandin, Simon; Schad, Lothar R. [Heidelberg Univ., Mannheim (Germany). Computer Assisted Clinical Medicine; Haneder, Stefan [Heidelberg Univ., Mannheim (Germany). Clinical Radiology and Nuclear Medicine; University Hospital of Cologne, Koeln (Germany). Dept. of Radiology

    2016-05-01

    Sodium magnetic resonance imaging ({sup 23}Na MRI) is a unique and non-invasive imaging technique which provides important information on cellular level about the tissue of the human body. Several applications for {sup 23}Na MRI were investigated with regard to the examination of the tissue viability and functionality for example in the brain, the heart or the breast. The {sup 23}Na MRI technique can also be integrated as a potential monitoring instrument after radiotherapy or chemotherapy. The main contribution in this work was the adaptation of {sup 23}Na MRI for spine imaging, which can provide essential information on the integrity of the intervertebral disks with respect to the early detection of disk degeneration. In this work, a transmit-only receive-only dual resonator system was designed and developed to cover the whole human spine using {sup 23}Na MRI and increase the receive sensitivity. The resonator system consisted of an already presented {sup 23}Na whole-body resonator and a newly developed 5-channel receive-only phased-array. The resonator system was first validated using bench top and phantom measurements. A threefold SNR improvement at the depth of the spine (∝7 cm) over the whole-body resonator was achieved using the spine array. {sup 23}Na MR measurements of the human spine using the transmit-only receive-only resonator system were performed on a healthy volunteer within an acquisition time of 10 minutes. A density adapted 3D radial sequence was chosen with 6 mm isotropic resolution, 49 ms repetition time and a short echo time of 540 μs. Furthermore, it was possible to quantify the tissue sodium concentration in the intervertebral discs in the lumbar region (120 ms repetition time) using this setup.

  20. Cocaine disinhibits dopamine neurons in the ventral tegmental area via use-dependent blockade of GABA neuron voltage-sensitive sodium channels.

    Science.gov (United States)

    Steffensen, Scott C; Taylor, Seth R; Horton, Malia L; Barber, Elise N; Lyle, Laura T; Stobbs, Sarah H; Allison, David W

    2008-11-01

    The aim of this study was to evaluate the effects of cocaine on gamma-aminobutyric acid (GABA) and dopamine (DA) neurons in the ventral tegmental area (VTA). Utilizing single-unit recordings in vivo, microelectrophoretic administration of DA enhanced the firing rate of VTA GABA neurons via D2/D3 DA receptor activation. Lower doses of intravenous cocaine (0.25-0.5 mg/kg), or the DA transporter (DAT) blocker methamphetamine, enhanced VTA GABA neuron firing rate via D2/D3 receptor activation. Higher doses of cocaine (1.0-2.0 mg/kg) inhibited their firing rate, which was not sensitive to the D2/D3 antagonist eticlopride. The voltage-sensitive sodium channel (VSSC) blocker lidocaine inhibited the firing rate of VTA GABA neurons at all doses tested (0.25-2.0 mg/kg). Cocaine or lidocaine reduced VTA GABA neuron spike discharges induced by stimulation of the internal capsule (ICPSDs) at dose levels 0.25-2 mg/kg (IC(50) 1.2 mg/kg). There was no effect of DA or methamphetamine on ICPSDs, or of DA antagonists on cocaine inhibition of ICPSDs. In VTA GABA neurons in vitro, cocaine reduced (IC(50) 13 microm) current-evoked spikes and TTX-sensitive sodium currents in a use-dependent manner. In VTA DA neurons, cocaine reduced IPSCs (IC(50) 13 microm), increased IPSC paired-pulse facilitation and decreased spontaneous IPSC frequency, without affecting miniature IPSC frequency or amplitude. These findings suggest that cocaine acts on GABA neurons to reduce activity-dependent GABA release on DA neurons in the VTA, and that cocaine's use-dependent blockade of VTA GABA neuron VSSCs may synergize with its DAT inhibiting properties to enhance mesolimbic DA transmission implicated in cocaine reinforcement.

  1. Sodium-23 MRI of whole spine at 3 Tesla using a 5-channel receive-only phased-array and a whole-body transmit resonator

    International Nuclear Information System (INIS)

    Sodium magnetic resonance imaging (23Na MRI) is a unique and non-invasive imaging technique which provides important information on cellular level about the tissue of the human body. Several applications for 23Na MRI were investigated with regard to the examination of the tissue viability and functionality for example in the brain, the heart or the breast. The 23Na MRI technique can also be integrated as a potential monitoring instrument after radiotherapy or chemotherapy. The main contribution in this work was the adaptation of 23Na MRI for spine imaging, which can provide essential information on the integrity of the intervertebral disks with respect to the early detection of disk degeneration. In this work, a transmit-only receive-only dual resonator system was designed and developed to cover the whole human spine using 23Na MRI and increase the receive sensitivity. The resonator system consisted of an already presented 23Na whole-body resonator and a newly developed 5-channel receive-only phased-array. The resonator system was first validated using bench top and phantom measurements. A threefold SNR improvement at the depth of the spine (∝7 cm) over the whole-body resonator was achieved using the spine array. 23Na MR measurements of the human spine using the transmit-only receive-only resonator system were performed on a healthy volunteer within an acquisition time of 10 minutes. A density adapted 3D radial sequence was chosen with 6 mm isotropic resolution, 49 ms repetition time and a short echo time of 540 μs. Furthermore, it was possible to quantify the tissue sodium concentration in the intervertebral discs in the lumbar region (120 ms repetition time) using this setup.

  2. Coordinated role of voltage-gated sodium channels and the Na{sup +}/H{sup +} exchanger in sustaining microglial activation during inflammation

    Energy Technology Data Exchange (ETDEWEB)

    Hossain, Muhammad M. [Department of Environmental and Occupational Medicine and Environmental and Occupational Health Sciences Institute, Rutgers Robert Wood Johnson Medical School, Piscataway, NJ (United States); Sonsalla, Patricia K. [Department of Neurology, Rutgers Robert Wood Johnson Medical School, Piscataway, NJ (United States); Richardson, Jason R., E-mail: jricha3@eohsi.rutgers.edu [Department of Environmental and Occupational Medicine and Environmental and Occupational Health Sciences Institute, Rutgers Robert Wood Johnson Medical School, Piscataway, NJ (United States)

    2013-12-01

    Persistent neuroinflammation and microglial activation play an integral role in the pathogenesis of many neurological disorders. We investigated the role of voltage-gated sodium channels (VGSC) and Na{sup +}/H{sup +} exchangers (NHE) in the activation of immortalized microglial cells (BV-2) after lipopolysaccharide (LPS) exposure. LPS (10 and 100 ng/ml) caused a dose- and time-dependent accumulation of intracellular sodium [(Na{sup +}){sub i}] in BV-2 cells. Pre-treatment of cells with the VGSC antagonist tetrodotoxin (TTX, 1 μM) abolished short-term Na{sup +} influx, but was unable to prevent the accumulation of (Na{sup +}){sub i} observed at 6 and 24 h after LPS exposure. The NHE inhibitor cariporide (1 μM) significantly reduced accumulation of (Na{sup +}){sub i} 6 and 24 h after LPS exposure. Furthermore, LPS increased the mRNA expression and protein level of NHE-1 in a dose- and time-dependent manner, which was significantly reduced after co-treatment with TTX and/or cariporide. LPS increased production of TNF-α, ROS, and H{sub 2}O{sub 2} and expression of gp91{sup phox}, an active subunit of NADPH oxidase, in a dose- and time-dependent manner, which was significantly reduced by TTX or TTX + cariporide. Collectively, these data demonstrate a closely-linked temporal relationship between VGSC and NHE-1 in regulating function in activated microglia, which may provide avenues for therapeutic interventions aimed at reducing neuroinflammation. - Highlights: • LPS causes immediate increase in sodium through VGSC and subsequently through the NHE-1. • Inhibition of VGSC reduces increases in NHE-1 and gp91{sup phox}. • Inhibition of VGSC and NHE-1 reduces NADPH oxidase-mediated Tnf-α, ROS, and H{sub 2}O{sub 2} production. • NHE-1 and Na{sub v}1.6 may be viable targets for therapeutic interventions to reduce neuroinflammation in neurodegenerative disease.

  3. Three Peptide Modulators of the Human Voltage-Gated Sodium Channel 1.7, an Important Analgesic Target, from the Venom of an Australian Tarantula

    Directory of Open Access Journals (Sweden)

    Chun Yuen Chow

    2015-06-01

    Full Text Available Voltage-gated sodium (NaV channels are responsible for propagating action potentials in excitable cells. NaV1.7 plays a crucial role in the human pain signalling pathway and it is an important therapeutic target for treatment of chronic pain. Numerous spider venom peptides have been shown to modulate the activity of NaV channels and these peptides represent a rich source of research tools and therapeutic lead molecules. The aim of this study was to determine the diversity of NaV1.7-active peptides in the venom of an Australian Phlogius sp. tarantula and to characterise their potency and subtype selectivity. We isolated three novel peptides, μ-TRTX-Phlo1a, -Phlo1b and -Phlo2a, that inhibit human NaV1.7 (hNaV1.7. Phlo1a and Phlo1b are 35-residue peptides that differ by one amino acid and belong in NaSpTx family 2. The partial sequence of Phlo2a revealed extensive similarity with ProTx-II from NaSpTx family 3. Phlo1a and Phlo1b inhibit hNaV1.7 with IC50 values of 459 and 360 nM, respectively, with only minor inhibitory activity on rat NaV1.2 and hNaV1.5. Although similarly potent at hNaV1.7 (IC50 333 nM, Phlo2a was less selective, as it also potently inhibited rNaV1.2 and hNaV1.5. All three peptides cause a depolarising shift in the voltage-dependence of hNaV1.7 activation.

  4. Three Peptide Modulators of the Human Voltage-Gated Sodium Channel 1.7, an Important Analgesic Target, from the Venom of an Australian Tarantula.

    Science.gov (United States)

    Chow, Chun Yuen; Cristofori-Armstrong, Ben; Undheim, Eivind A B; King, Glenn F; Rash, Lachlan D

    2015-07-01

    Voltage-gated sodium (NaV) channels are responsible for propagating action potentials in excitable cells. NaV1.7 plays a crucial role in the human pain signalling pathway and it is an important therapeutic target for treatment of chronic pain. Numerous spider venom peptides have been shown to modulate the activity of NaV channels and these peptides represent a rich source of research tools and therapeutic lead molecules. The aim of this study was to determine the diversity of NaV1.7-active peptides in the venom of an Australian Phlogius sp. tarantula and to characterise their potency and subtype selectivity. We isolated three novel peptides, μ-TRTX-Phlo1a, -Phlo1b and -Phlo2a, that inhibit human NaV1.7 (hNaV1.7). Phlo1a and Phlo1b are 35-residue peptides that differ by one amino acid and belong in NaSpTx family 2. The partial sequence of Phlo2a revealed extensive similarity with ProTx-II from NaSpTx family 3. Phlo1a and Phlo1b inhibit hNaV1.7 with IC50 values of 459 and 360 nM, respectively, with only minor inhibitory activity on rat NaV1.2 and hNaV1.5. Although similarly potent at hNaV1.7 (IC50 333 nM), Phlo2a was less selective, as it also potently inhibited rNaV1.2 and hNaV1.5. All three peptides cause a depolarising shift in the voltage-dependence of hNaV1.7 activation. PMID:26134258

  5. Structural Properties and Charge Distribution of the Sodium Uranium, Neptunium, and Plutonium Ternary Oxides: A Combined X-ray Diffraction and XANES Study.

    Science.gov (United States)

    Smith, Anna L; Martin, Philippe; Prieur, Damien; Scheinost, Andreas C; Raison, Philippe E; Cheetham, Anthony K; Konings, Rudy J M

    2016-02-15

    The charge distributions in α-Na2UO4, Na3NpO4, α-Na2NpO4, Na4NpO5, Na5NpO6, Na2PuO3, Na4PuO5, and Na5PuO6 are investigated in this work using X-ray absorption near-edge structure (XANES) spectroscopy at the U-L3, Np-L3, and Pu-L3 edges. In addition, a Rietveld refinement of monoclinic Na2PuO3, in space group C2/c, is reported for the first time, and the existence of the isostructural Na2NpO3 phase is revealed. In contrast to measurements in solution, the number of published XANES data for neptunium and plutonium solid phases with a valence state higher than IV is very limited. The present results cover a wide range of oxidation states, namely, IV to VII, and can serve as reference for future investigations. The sodium actinide series show a variety of local coordination geometries, and correlations between the shape of the XANES spectra and the local structural environments are discussed herein. PMID:26835549

  6. QSAR analyses of DDT analogues and their in silico validation using molecular docking study against voltage-gated sodium channel of Anopheles funestus.

    Science.gov (United States)

    Saini, V; Kumar, A

    2014-01-01

    DDT has enjoyed the reputation of a successful pesticide in disease control programme and agricultural practices along with the serious opposition and ban later on due to its biomagnification and toxic action against non-target organisms. The present work was carried out to develop QSAR models for analysing DDT analogues for their pesticidal activity and in silico validation of these models. A 2D-QSAR model was generated using stepwise with multiple regression, and the model with a value of r(2) = 0.7324; q(2) = 0.6215; pred r(2) = 0.7038, containing five descriptors, was selected for further study. The 3D QSAR with CoMFA analysis showed that steric contribution of 21% and electrostatic contribution of about 79% were required for larvicidal activity of DDT analogues. A set of 3430 molecules was generated using the basic DDT skeleton as template, and these were evaluated for their mosquito larvicidal activity using the generated QSAR models and DDT as standard. Eleven molecules were selected for in silico validation of these models. For this, a docking study of the selected molecules against the homology-modelled voltage-gated sodium channel of Anopheles funestus was conducted. The study showed that the activities of these analogues as predicted by 2D-QSAR, 3D-QSAR with CoMFA and dock score were observed to be well correlated.

  7. High-density SNP screen of sodium channel genes by haplotype tagging and DNA pooling for association with idiopathic generalized epilepsy.

    Science.gov (United States)

    Makoff, Andrew; Lai, Teck; Barratt, Catherine; Valentin, Antonio; Moran, Nick; Asherson, Philip; Nashef, Lina

    2010-04-01

    We have investigated seven voltage-gated sodium channel genes for association with idiopathic generalized epilepsy (IGE). Probands and control DNA were grouped into pools and used to screen 85 single-nucleotide polymorphisms (SNPs), mostly HapMap SNPs tagging the common variation in these genes. Twelve SNPs exhibiting an allele frequency difference between pools were genotyped individually in our sample of 232 probands, 313 controls, and 95 parent-proband trios. Two SNPs, in SCN1A and SCN8A, were associated by allele and genotype at nominal level of significance, but were not significant after Bonferroni correction. Two SCN2A SNPs (rs3943809 and rs16850331) were associated by case-control with a subgroup with IGE and history of febrile seizures and also by transmission disequilibrium test (TDT) in parent-proband trios. Both SNPs are part of a linkage disequilibrium (LD) cluster of 38 SNPs, but none are obvious functional variants. The association of rs3943809 with the febrile seizure subgroup (p = 0.0004) remains significant after the conservative Bonferroni correction for multiple testing.

  8. Docking Simulation of the Binding Interactions of Saxitoxin Analogs Produced by the Marine Dinoflagellate Gymnodinium catenatum to the Voltage-Gated Sodium Channel Nav1.4

    Directory of Open Access Journals (Sweden)

    Lorena M. Durán-Riveroll

    2016-05-01

    Full Text Available Saxitoxin (STX and its analogs are paralytic alkaloid neurotoxins that block the voltage-gated sodium channel pore (Nav, impeding passage of Na+ ions into the intracellular space, and thereby preventing the action potential in the peripheral nervous system and skeletal muscle. The marine dinoflagellate Gymnodinium catenatum produces an array of such toxins, including the recently discovered benzoyl analogs, for which the mammalian toxicities are essentially unknown. We subjected STX and its analogs to a theoretical docking simulation based upon two alternative tri-dimensional models of the Nav1.4 to find a relationship between the binding properties and the known mammalian toxicity of selected STX analogs. We inferred hypothetical toxicities for the benzoyl analogs from the modeled values. We demonstrate that these toxins exhibit different binding modes with similar free binding energies and that these alternative binding modes are equally probable. We propose that the principal binding that governs ligand recognition is mediated by electrostatic interactions. Our simulation constitutes the first in silico modeling study on benzoyl-type paralytic toxins and provides an approach towards a better understanding of the mode of action of STX and its analogs.

  9. Docking Simulation of the Binding Interactions of Saxitoxin Analogs Produced by the Marine Dinoflagellate Gymnodinium catenatum to the Voltage-Gated Sodium Channel Nav1.4

    Science.gov (United States)

    Durán-Riveroll, Lorena M.; Cembella, Allan D.; Band-Schmidt, Christine J.; Bustillos-Guzmán, José J.; Correa-Basurto, José

    2016-01-01

    Saxitoxin (STX) and its analogs are paralytic alkaloid neurotoxins that block the voltage-gated sodium channel pore (Nav), impeding passage of Na+ ions into the intracellular space, and thereby preventing the action potential in the peripheral nervous system and skeletal muscle. The marine dinoflagellate Gymnodinium catenatum produces an array of such toxins, including the recently discovered benzoyl analogs, for which the mammalian toxicities are essentially unknown. We subjected STX and its analogs to a theoretical docking simulation based upon two alternative tri-dimensional models of the Nav1.4 to find a relationship between the binding properties and the known mammalian toxicity of selected STX analogs. We inferred hypothetical toxicities for the benzoyl analogs from the modeled values. We demonstrate that these toxins exhibit different binding modes with similar free binding energies and that these alternative binding modes are equally probable. We propose that the principal binding that governs ligand recognition is mediated by electrostatic interactions. Our simulation constitutes the first in silico modeling study on benzoyl-type paralytic toxins and provides an approach towards a better understanding of the mode of action of STX and its analogs. PMID:27164145

  10. QSAR analyses of DDT analogues and their in silico validation using molecular docking study against voltage-gated sodium channel of Anopheles funestus.

    Science.gov (United States)

    Saini, V; Kumar, A

    2014-01-01

    DDT has enjoyed the reputation of a successful pesticide in disease control programme and agricultural practices along with the serious opposition and ban later on due to its biomagnification and toxic action against non-target organisms. The present work was carried out to develop QSAR models for analysing DDT analogues for their pesticidal activity and in silico validation of these models. A 2D-QSAR model was generated using stepwise with multiple regression, and the model with a value of r(2) = 0.7324; q(2) = 0.6215; pred r(2) = 0.7038, containing five descriptors, was selected for further study. The 3D QSAR with CoMFA analysis showed that steric contribution of 21% and electrostatic contribution of about 79% were required for larvicidal activity of DDT analogues. A set of 3430 molecules was generated using the basic DDT skeleton as template, and these were evaluated for their mosquito larvicidal activity using the generated QSAR models and DDT as standard. Eleven molecules were selected for in silico validation of these models. For this, a docking study of the selected molecules against the homology-modelled voltage-gated sodium channel of Anopheles funestus was conducted. The study showed that the activities of these analogues as predicted by 2D-QSAR, 3D-QSAR with CoMFA and dock score were observed to be well correlated. PMID:25271473

  11. Aptiom (eslicarbazepine acetate) as a dual inhibitor of β-secretase and voltage-gated sodium channel: advancement in Alzheimer's disease-epilepsy linkage via an enzoinformatics study.

    Science.gov (United States)

    Shaikh, Sibhghatulla; Rizvi, Syed M D; Hameed, Nida; Biswas, Deboshree; Khan, Mahiuddin; Shakil, Shazi; Kamal, Mohammad A

    2014-01-01

    Neurodegenerative disorders are increasingly identified as one of the major causes of epilepsy. The relationship of epileptic activity to Alzheimer's disease (AD) is of clinical importance. Voltage-gated sodium channel (VSC) is one of the best targets in the treatment of epilepsy while β-secretase (BACE) has long been observed as a curative target for AD. To explore a possible link between the treatment of AD and epilepsy, the molecular interactions of recently Food and Drug Administration approved antiepileptic drug Aptiom (Eslicarbazepine acetate) with BACE and VSC were studied. Docking study was performed using 'Autodock4.2'. Hydrophobic and pi-pi interactions play critical role in the correct positioning of Eslicarbazepine acetate within the catalytic site of VSC and BACE enzyme to permit docking. Free energy of binding (ΔG) of 'Eslicarbazepine acetate-VSC' interaction and 'Eslicarbazepine acetate-CAS domain of BACE' interaction was found to be -5.97 and -7.19 kcal/mol, respectively. Hence, Eslicarbazepine acetate might act as a potent dual inhibitor of BACE and VSC. However, scope still remains in the determination of the three-dimensional structure of BACE-Eslicarbazepine acetate and VSC-Eslicarbazepine acetate complexes by X-ray crystallography to validate the described data. Further, Aptiom (Eslicarbazepine acetate) could be expected to form the basis of future dual therapy against epilepsy associated neurological disorders. PMID:25230222

  12. A recombinant fusion protein containing a spider toxin specific for the insect voltage-gated sodium ion channel shows oral toxicity towards insects of different orders.

    Science.gov (United States)

    Yang, Sheng; Pyati, Prashant; Fitches, Elaine; Gatehouse, John A

    2014-04-01

    Recombinant fusion protein technology allows specific insecticidal protein and peptide toxins to display activity in orally-delivered biopesticides. The spider venom peptide δ-amaurobitoxin-PI1a, which targets insect voltage-gated sodium channels, was fused to the "carrier" snowdrop lectin (GNA) to confer oral toxicity. The toxin itself (PI1a) and an amaurobitoxin/GNA fusion protein (PI1a/GNA) were produced using the yeast Pichia pastoris as expression host. Although both proteins caused mortality when injected into cabbage moth (Mamestra brassicae) larvae, the PI1a/GNA fusion was approximately 6 times as effective as recombinant PI1a on a molar basis. PI1a alone was not orally active against cabbage moth larvae, but a single 30 μg dose of the PI1a/GNA fusion protein caused 100% larval mortality within 6 days when fed to 3rd instar larvae, and caused significant reductions in survival, growth and feeding in 4th - 6th instar larvae. Transport of fusion protein from gut contents to the haemolymph of cabbage moth larvae, and binding to the nerve chord, was shown by Western blotting. The PI1a/GNA fusion protein also caused mortality when delivered orally to dipteran (Musca domestica; housefly) and hemipteran (Acyrthosiphon pisum; pea aphid) insects, making it a promising candidate for development as a biopesticide. PMID:24486516

  13. Investigations of the Navβ1b sodium channel subunit in human ventricle; functional characterization of the H162P Brugada Syndrome mutant

    DEFF Research Database (Denmark)

    Yuan, Lei; Koivumaki, Jussi; Liang, Bo;

    2014-01-01

    Brugada Syndrome (BrS) is a rare inherited disease which can give rise to ventricular arrhythmia and ultimately sudden cardiac death. Numerous loss-of-function mutations in the cardiac sodium channel Nav1.5 have been associated with BrS. However, few mutations in the auxiliary Navβ1-4 subunits have...... been linked to this disease. Here we investigated differences in expression and function between Navβ1 and Navβ1b, and whether the H162P/Navβ1b mutation found in a BrS patient is likely to be the underlying cause of disease. The impact of Navβ-subunits were investigated by patch-clamp electrophysiology...... and the obtained in vitro values were used for subsequent in silico modeling. We found that Navβ1b transcripts were expressed at higher levels than Navβ1 transcripts in the human heart. Navβ1b was found to increase the current level when co-expressed with Nav1.5, the Navβ1b/H162P mutated subunit peak current...

  14. Effects of (−-Gallocatechin-3-Gallate on Tetrodotoxin-Resistant Voltage-Gated Sodium Channels in Rat Dorsal Root Ganglion Neurons

    Directory of Open Access Journals (Sweden)

    Jian-Min Jiang

    2013-05-01

    Full Text Available The (−-gallocatechin-3-gallate (GCG concentration in some tea beverages can account for as much as 50% of the total catechins. It has been shown that catechins have analgesic properties. Voltage-gated sodium channels (Nav mediate neuronal action potentials. Tetrodotoxin inhibits all Nav isoforms, but Nav1.8 and Nav1.9 are relatively tetrodotoxin-resistant compared to other isoforms and functionally linked to nociception. In this study, the effects of GCG on tetrodotoxin-resistant Na+ currents were investigated in rat primary cultures of dorsal root ganglion neurons via the whole-cell patch-clamp technique. We found that 1 μM GCG reduced the amplitudes of peak current density of tetrodotoxin-resistant Na+ currents significantly. Furthermore, the inhibition was accompanied by a depolarizing shift of the activation voltage and a hyperpolarizing shift of steady-state inactivation voltage. The percentage block of GCG (1 μM on tetrodotoxin-resistant Na+ current was 45.1% ± 1.1% in 10 min. In addition, GCG did not produce frequency-dependent block of tetrodotoxin-resistant Na+ currents at stimulation frequencies of 1 Hz, 2 Hz and 5 Hz. On the basis of these findings, we propose that GCG may be a potential analgesic agent.

  15. Sustained inhibition of the NaV1.7 sodium channel by engineered dimers of the domain II binding peptide GpTx-1.

    Science.gov (United States)

    Murray, Justin K; Biswas, Kaustav; Holder, J Ryan; Zou, Anruo; Ligutti, Joseph; Liu, Dong; Poppe, Leszek; Andrews, Kristin L; Lin, Fen-Fen; Meng, Shi-Yuan; Moyer, Bryan D; McDonough, Stefan I; Miranda, Les P

    2015-11-01

    Many efforts are underway to develop selective inhibitors of the voltage-gated sodium channel NaV1.7 as new analgesics. Thus far, however, in vitro selectivity has proved difficult for small molecules, and peptides generally lack appropriate pharmacokinetic properties. We previously identified the NaV1.7 inhibitory peptide GpTx-1 from tarantula venom and optimized its potency and selectivity via structure-guided analoging. To further understand GpTx-1 binding to NaV1.7, we have mapped the binding site to transmembrane segments 1-4 of the second pseudosubunit internal repeat (commonly referred to as Site 4) using NaV1.5/NaV1.7 chimeric protein constructs. We also report that select GpTx-1 amino acid residues apparently not contacting NaV1.7 can be derivatized with a hydrophilic polymer without adversely affecting peptide potency. Homodimerization of GpTx-1 with a bifunctional polyethylene glycol (PEG) linker resulted in a compound with increased potency and a significantly reduced off-rate, demonstrating the ability to modulate the function and properties of GpTx-1 by linking to additional molecules. PMID:26112439

  16. Engineering potent and selective analogues of GpTx-1, a tarantula venom peptide antagonist of the Na(V)1.7 sodium channel.

    Science.gov (United States)

    Murray, Justin K; Ligutti, Joseph; Liu, Dong; Zou, Anruo; Poppe, Leszek; Li, Hongyan; Andrews, Kristin L; Moyer, Bryan D; McDonough, Stefan I; Favreau, Philippe; Stöcklin, Reto; Miranda, Les P

    2015-03-12

    NaV1.7 is a voltage-gated sodium ion channel implicated by human genetic evidence as a therapeutic target for the treatment of pain. Screening fractionated venom from the tarantula Grammostola porteri led to the identification of a 34-residue peptide, termed GpTx-1, with potent activity on NaV1.7 (IC50 = 10 nM) and promising selectivity against key NaV subtypes (20× and 1000× over NaV1.4 and NaV1.5, respectively). NMR structural analysis of the chemically synthesized three disulfide peptide was consistent with an inhibitory cystine knot motif. Alanine scanning of GpTx-1 revealed that residues Trp(29), Lys(31), and Phe(34) near the C-terminus are critical for potent NaV1.7 antagonist activity. Substitution of Ala for Phe at position 5 conferred 300-fold selectivity against NaV1.4. A structure-guided campaign afforded additive improvements in potency and NaV subtype selectivity, culminating in the design of [Ala5,Phe6,Leu26,Arg28]GpTx-1 with a NaV1.7 IC50 value of 1.6 nM and >1000× selectivity against NaV1.4 and NaV1.5. PMID:25658507

  17. Hydrogen sulfide prevents hydrogen peroxide-induced activation of epithelial sodium channel through a PTEN/PI(3,4,5P3 dependent pathway.

    Directory of Open Access Journals (Sweden)

    Jianing Zhang

    Full Text Available Sodium reabsorption through the epithelial sodium channel (ENaC at the distal segment of the kidney plays an important role in salt-sensitive hypertension. We reported previously that hydrogen peroxide (H2O2 stimulates ENaC in A6 distal nephron cells via elevation of phosphatidylinositol 3,4,5-trisphosphate (PI(3,4,5P3 in the apical membrane. Here we report that H2S can antagonize H2O2-induced activation of ENaC in A6 cells. Our cell-attached patch-clamp data show that ENaC open probability (PO was significantly increased by exogenous H2O2, which is consistent with our previous finding. The aberrant activation of ENaC induced by exogenous H2O2 was completely abolished by H2S (0.1 mM NaHS. Pre-treatment of A6 cells with H2S slightly decreased ENaC P(O; however, in these cells H2O2 failed to elevate ENaC PO . Confocal microscopy data show that application of exogenous H2O2 to A6 cells significantly increased intracellular reactive oxygen species (ROS level and induced accumulation of PI(3,4,5P3 in the apical compartment of the cell membrane. These effects of exogenous H2O2 on intracellular ROS levels and on apical PI(3,4,5P3 levels were almost completely abolished by treatment of A6 cells with H2S. In addition, H2S significantly inhibited H2O2-induced oxidative inactivation of the tumor suppressor phosphatase and tensin homolog (PTEN which is a negative regulator of PI(3,4,5P3. Moreover, BPV(pic, a specific inhibitor of PTEN, elevated PI(3,4,5P3 and ENaC activity in a manner similar to that of H2O2 in A6 cells. Our data show, for the first time, that H2S prevents H2O2-induced activation of ENaC through a PTEN-PI(3,4,5P3 dependent pathway.

  18. Strong suppression of nuclear-charge changing interactions for 18 TeV/ c In ions channeled through a bent Si crystal

    Science.gov (United States)

    Uggerhøj, U. I.; Hansen, H. D.; Jessen, K.; Knudsen, H.; Uggerhøj, E.; Scheidenberger, C.; Biino, C.; Clément, M.; Doble, N.; Elsener, K.; Gatignon, L.; Grafström, P.; Sona, P.; Mangiarotti, A.; Ballestrero, S.

    2005-07-01

    We present experimental results giving evidence for the strong reduction-a factor of more than 20-of nuclear-charge changing interactions for 18 TeV In49+ ions channeled through a silicon crystal bent to 7.5, 11.9 and 19.8 mrad. A very small fraction of the deflected ions suffer electromagnetic or nuclear interactions leading to proton loss while traversing the 60 mm long crystal, even though its thickness corresponds to about 0.13 nuclear interaction lengths for an amorphous material. By considering the deflected ions only, we show experimentally that the nuclear-charge pickup reaction believed to be induced by virtual photons is a short-range phenomenon.

  19. Strong suppression of nuclear-charge changing interactions for 18 TeV/c In ions channeled through a bent Si crystal

    Energy Technology Data Exchange (ETDEWEB)

    Uggerhoj, U.I. [Department of Physics and Astronomy, University of Aarhus (Denmark)]. E-mail: ulrik@phys.au.dk; Hansen, H.D. [Department of Physics and Astronomy, University of Aarhus (Denmark); Jessen, K. [Department of Physics and Astronomy, University of Aarhus (Denmark); Knudsen, H. [Department of Physics and Astronomy, University of Aarhus (Denmark); Uggerhoj, E. [Department of Physics and Astronomy, University of Aarhus (Denmark); Scheidenberger, C. [GSI, Darmstadt (Germany); Biino, C. [CERN, Geneva (Switzerland); Clement, M. [CERN, Geneva (Switzerland); Doble, N. [CERN, Geneva (Switzerland); Elsener, K. [CERN, Geneva (Switzerland); Gatignon, L. [CERN, Geneva (Switzerland); Grafstroem, P. [CERN, Geneva (Switzerland); Sona, P. [University of Florence, Florence (Italy); Mangiarotti, A. [University of Florence, Florence (Italy); Ballestrero, S. [University of Florence, Florence (Italy)

    2005-07-21

    We present experimental results giving evidence for the strong reduction-a factor of more than 20-of nuclear-charge changing interactions for 18 TeV In{sup 49+} ions channeled through a silicon crystal bent to 7.5, 11.9 and 19.8 mrad. A very small fraction of the deflected ions suffer electromagnetic or nuclear interactions leading to proton loss while traversing the 60 mm long crystal, even though its thickness corresponds to about 0.13 nuclear interaction lengths for an amorphous material. By considering the deflected ions only, we show experimentally that the nuclear-charge pickup reaction believed to be induced by virtual photons is a short-range phenomenon.

  20. Sodium Azide

    Science.gov (United States)

    ... Matters What's New A - Z Index Facts About Sodium Azide What sodium azide is Sodium azide is a rapidly acting, ... give people sufficient warning of the danger. Where sodium azide is found and how it is used ...

  1. Role of voltage-sodium channels in neuropathic pain%钠离子通道在神经病理性疼痛中的作用研究进展

    Institute of Scientific and Technical Information of China (English)

    寿雯婷; 张世红; 陈忠

    2011-01-01

    Voltage-gated sodium channels are critical for the generation and conduction of nerve impulses. Recent studies show that in primary sensory neurons, the expression and dynamic regulation of several sodium channel subtypes play important roles in neuropathic pain. A number of SCN9A (encoding Nav1.7) gene point mutations are related with human genetic pain disorders. Transgenic and specific knockout techniques have revealed that Nav1. 3, Nav1. 8, Nav1. 9 are important for the development and maintenance of neuropathic pain condition. Specific blockers of these sodium channels have been demonstrated to be effective in alleviating allodynia and hyperalgesia. Here we reviewed the roles of sodium channels in neuropathic pain, which may be applicable for the development of new drugs with enhanced efficacy for neuropathic pain treatment.%多种钠离子通道亚型在初级感觉神经元中的表达及动态调节,影响神经病理性疼痛的发生、发展及维持过程.SCN9A基因(编码Navl.7)的多个位点突变被认为与人类多种可遗传的疼痛疾病密切相关.转基因技术和特异性敲除技术的应用发现,Navl.3、Navl.8和Navl.9在神经病理性疼痛的发生和维持方面起到重要的作用.因此,研究电压依赖性钠离子通道在神经病理性疼痛中的作用,有利于揭示该种疾病的发生和维持机制,也可为开发新一代镇痛药物提供理论依据.

  2. Roles of Voltage-Gated Tetrodotoxin-Sensitive Sodium Channels NaV1.3 and NaV1.7 in Diabetes and Painful Diabetic Neuropathy.

    Science.gov (United States)

    Yang, Linlin; Li, Quanmin; Liu, Xinming; Liu, Shiguang

    2016-01-01

    Diabetes mellitus (DM) is a common chronic medical problem worldwide; one of its complications is painful peripheral neuropathy, which can substantially erode quality of life and increase the cost of management. Despite its clinical importance, the pathogenesis of painful diabetic neuropathy (PDN) is complex and incompletely understood. Voltage-gated sodium channels (VGSCs) link many physiological processes to electrical activity by controlling action potentials in all types of excitable cells. Two isoforms of VGSCs, NaV1.3 and NaV1.7, which are encoded by the sodium voltage-gated channel alpha subunit 3 and 9 (Scn3A and Scn9A) genes, respectively, have been identified in both peripheral nociceptive neurons of dorsal root ganglion (DRG) and pancreatic islet cells. Recent advances in our understanding of tetrodotoxin-sensitive (TTX-S) sodium channels NaV1.3 and NaV1.7 lead to the rational doubt about the cause-effect relation between diabetes and painful neuropathy. In this review, we summarize the roles of NaV1.3 and NaV1.7 in islet cells and DRG neurons, discuss the link between DM and painful neuropathy, and present a model, which may provide a starting point for further studies aimed at identifying the mechanisms underlying diabetes and painful neuropathy. PMID:27608006

  3. Roles of Voltage-Gated Tetrodotoxin-Sensitive Sodium Channels NaV1.3 and NaV1.7 in Diabetes and Painful Diabetic Neuropathy

    Science.gov (United States)

    Yang, Linlin; Li, Quanmin; Liu, Xinming; Liu, Shiguang

    2016-01-01

    Diabetes mellitus (DM) is a common chronic medical problem worldwide; one of its complications is painful peripheral neuropathy, which can substantially erode quality of life and increase the cost of management. Despite its clinical importance, the pathogenesis of painful diabetic neuropathy (PDN) is complex and incompletely understood. Voltage-gated sodium channels (VGSCs) link many physiological processes to electrical activity by controlling action potentials in all types of excitable cells. Two isoforms of VGSCs, NaV1.3 and NaV1.7, which are encoded by the sodium voltage-gated channel alpha subunit 3 and 9 (Scn3A and Scn9A) genes, respectively, have been identified in both peripheral nociceptive neurons of dorsal root ganglion (DRG) and pancreatic islet cells. Recent advances in our understanding of tetrodotoxin-sensitive (TTX-S) sodium channels NaV1.3 and NaV1.7 lead to the rational doubt about the cause–effect relation between diabetes and painful neuropathy. In this review, we summarize the roles of NaV1.3 and NaV1.7 in islet cells and DRG neurons, discuss the link between DM and painful neuropathy, and present a model, which may provide a starting point for further studies aimed at identifying the mechanisms underlying diabetes and painful neuropathy. PMID:27608006

  4. Roles of Voltage-Gated Tetrodotoxin-Sensitive Sodium Channels NaV1.3 and NaV1.7 in Diabetes and Painful Diabetic Neuropathy

    Directory of Open Access Journals (Sweden)

    Linlin Yang

    2016-09-01

    Full Text Available Diabetes mellitus (DM is a common chronic medical problem worldwide; one of its complications is painful peripheral neuropathy, which can substantially erode quality of life and increase the cost of management. Despite its clinical importance, the pathogenesis of painful diabetic neuropathy (PDN is complex and incompletely understood. Voltage-gated sodium channels (VGSCs link many physiological processes to electrical activity by controlling action potentials in all types of excitable cells. Two isoforms of VGSCs, NaV1.3 and NaV1.7, which are encoded by the sodium voltage-gated channel alpha subunit 3 and 9 (Scn3A and Scn9A genes, respectively, have been identified in both peripheral nociceptive neurons of dorsal root ganglion (DRG and pancreatic islet cells. Recent advances in our understanding of tetrodotoxin-sensitive (TTX-S sodium channels NaV1.3 and NaV1.7 lead to the rational doubt about the cause–effect relation between diabetes and painful neuropathy. In this review, we summarize the roles of NaV1.3 and NaV1.7 in islet cells and DRG neurons, discuss the link between DM and painful neuropathy, and present a model, which may provide a starting point for further studies aimed at identifying the mechanisms underlying diabetes and painful neuropathy.

  5. Differential state-dependent modification of rat Na{sub v}1.6 sodium channels expressed in human embryonic kidney (HEK293) cells by the pyrethroid insecticides tefluthrin and deltamethrin

    Energy Technology Data Exchange (ETDEWEB)

    He, Bingjun [College of Life Sciences, Nankai University, Tianjin 300071 (China); Soderlund, David M., E-mail: dms6@cornell.edu [Department of Entomology, Cornell University, New York State Agricultural Experiment Station, Geneva, NY 14456 (United States)

    2011-12-15

    We expressed rat Na{sub v}1.6 sodium channels in combination with the rat {beta}1 and {beta}2 auxiliary subunits in human embryonic kidney (HEK293) cells and evaluated the effects of the pyrethroid insecticides tefluthrin and deltamethrin on expressed sodium currents using the whole-cell patch clamp technique. Both pyrethroids produced concentration-dependent, resting modification of Na{sub v}1.6 channels, prolonging the kinetics of channel inactivation and deactivation to produce persistent 'late' currents during depolarization and tail currents following repolarization. Both pyrethroids also produced concentration dependent hyperpolarizing shifts in the voltage dependence of channel activation and steady-state inactivation. Maximal shifts in activation, determined from the voltage dependence of the pyrethroid-induced late and tail currents, were {approx} 25 mV for tefluthrin and {approx} 20 mV for deltamethrin. The highest attainable concentrations of these compounds also caused shifts of {approx} 5-10 mV in the voltage dependence of steady-state inactivation. In addition to their effects on the voltage dependence of inactivation, both compounds caused concentration-dependent increases in the fraction of sodium current that was resistant to inactivation following strong depolarizing prepulses. We assessed the use-dependent effects of tefluthrin and deltamethrin on Na{sub v}1.6 channels by determining the effect of trains of 1 to 100 5-ms depolarizing prepulses at frequencies of 20 or 66.7 Hz on the extent of channel modification. Repetitive depolarization at either frequency increased modification by deltamethrin by {approx} 2.3-fold but had no effect on modification by tefluthrin. Tefluthrin and deltamethrin were equally potent as modifiers of Na{sub v}1.6 channels in HEK293 cells using the conditions producing maximal modification as the basis for comparison. These findings show that the actions of tefluthrin and deltamethrin of Na{sub v}1.6 channels

  6. [The effect of charged local anesthetics on the inactivation of Ca2+-activated Cl-channels of characean algae].

    Science.gov (United States)

    Kataev, A A; Zherelova, O M; Berestovskiĭ, G N

    1988-01-01

    Effects of local anesthetics (LA) and a number of organic cations on Ca2+-activated Cl-channels in plasmalemma of intracellularly perfused giant algae Nitellopsis obtusa were studied using voltage-clamp technique. It was shown earlier that Ca2+ ions cause irreversible inactivation of Cl-channels with a characteristic time equal to a few minutes, but not only activate Cl-channels. It has been found that amphiphilic cations (AC), including LA+, introduced intracellularly together with Ca2+ produced delayed action on the beginning of the inactivation process (approximately ten minutes) producing no effect on activation during this period. The time of delayed action was linearly dependent on the concentrations ratio alpha = [AC]/[Ca2+]. Procaine is the most effective agent in this respect, the time of its delayed action on the inactivation process being 20 min at alpha = 1. LA in the neural form, hydrophilic AC of tetraethylammonium, as well as LA+ from the outside had no effect on Cl-channels. Cl-channels inactivated "irreversibly" by Ca2+ ions may be restored after addition of AC in Ca2+-containing perfusion medium. PMID:2470412

  7. Sodium Channel Voltage-Gated Beta 2 Plays a Vital Role in Brain Aging Associated with Synaptic Plasticity and Expression of COX5A and FGF-2.

    Science.gov (United States)

    XiYang, Yan-Bin; Wang, You-Cui; Zhao, Ya; Ru, Jin; Lu, Bing-Tuan; Zhang, Yue-Ning; Wang, Nai-Chao; Hu, Wei-Yan; Liu, Jia; Yang, Jin-Wei; Wang, Zhao-Jun; Hao, Chun-Guang; Feng, Zhong-Tang; Xiao, Zhi-Cheng; Dong, Wei; Quan, Xiong-Zhi; Zhang, Lian-Feng; Wang, Ting-Hua

    2016-03-01

    The role of sodium channel voltage-gated beta 2 (SCN2B) in brain aging is largely unknown. The present study was therefore designed to determine the role of SCN2B in brain aging by using the senescence-accelerated mice prone 8 (SAMP8), a brain senescence-accelerated animal model, together with the SCN2B transgenic mice. The results showed that SAMP8 exhibited impaired learning and memory functions, assessed by the Morris water maze test, as early as 8 months of age. The messenger RNA (mRNA) and protein expressions of SCN2B were also upregulated in the prefrontal cortex at this age. Treatment with traditional Chinese anti-aging medicine Xueshuangtong (Panax notoginseng saponins, PNS) significantly reversed the SCN2B expressions in the prefrontal cortex, resulting in improved learning and memory. Moreover, SCN2B knockdown transgenic mice were generated and bred to determine the roles of SCN2B in brain senescence. A reduction in the SCN2B level by 60.68% resulted in improvement in the hippocampus-dependent spatial recognition memory and long-term potential (LTP) slope of field excitatory postsynaptic potential (fEPSP), followed by an upregulation of COX5A mRNA levels and downregulation of fibroblast growth factor-2 (FGF-2) mRNA expression. Together, the present findings indicated that SCN2B could play an important role in the aging-related cognitive deterioration, which is associated with the regulations of COX5A and FGF-2. These findings could provide the potential strategy of candidate target to develop antisenescence drugs for the treatment of brain aging. PMID:25575679

  8. β1- and β3- voltage-gated sodium channel subunits modulate cell surface expression and glycosylation of Nav1.7 in HEK293 cells

    Directory of Open Access Journals (Sweden)

    Cedric James Laedermann

    2013-08-01

    Full Text Available Voltage-gated sodium channels (Navs are glycoproteins composed of a pore-forming α-subunit and associated β-subunits that regulate Nav α-subunit plasma membrane density and biophysical properties. Glycosylation of the Nav α-subunit also directly affects Navs gating. β-subunits and glycosylation thus comodulate Nav α-subunit gating. We hypothesized that β-subunits could directly influence α-subunit glycosylation. Whole-cell patch clamp of HEK293 cells revealed that both β1- and β3-subunits coexpression shifted V1/2 of steady-state activation and inactivation and increased Nav1.7-mediated INa density. Biotinylation of cell surface proteins, combined with the use of deglycosydases, confirmed that Nav1.7 α-subunits exist in multiple glycosylated states. The α-subunit intracellular fraction was found in a core-glycosylated state, migrating at approximately 250 kDa. At the plasma membrane, in addition to the core-glycosylated form, a fully glycosylated form of Nav1.7 (~280 kDa was observed. This higher band shifted to an intermediate band (~260 kDa when β1-subunits were coexpressed, suggesting that the β1-subunit promotes an alternative glycosylated form of Nav1.7. Furthermore, the β1-subunit increased the expression of this alternative glycosylated form and the β3-subunit increased the expression of the core-glycosylated form of Nav1.7. This study describes a novel role for β1- and β3-subunits in the modulation of Nav1.7 α-subunit glycosylation and cell surface expression.

  9. 呼吸道上皮细胞钠/氯离子通道与支气管哮喘%Epithelial sodium and chloride channels and bronchial asthma

    Institute of Scientific and Technical Information of China (English)

    王雯; 吉宏龙

    2015-01-01

    支气管哮喘(简称哮喘)是一种慢性气道疾病,表现为气道高反应性和气道炎症导致的可逆性气道阻塞.研究显示,呼吸道上皮细胞钠/氯离子通道(ENaC/CFTR)调节黏液纤毛系统从而参与了慢性气道疾病的发病机制.ENaC及CFTR共同调节黏液的水质层,从而影响气道纤毛清除能力.调节上皮通道蛋白的特异性拮抗剂或激活剂将为哮喘和其他慢性气道疾病的预防和治疗开拓新的研究前景.%Bronchial asthma (asthma) is a chronic respiratory disease characterized by reversible airway obstruction with bronchial hyper-responsiveness and inflammation.Airway cilia system is implicated in the pathogenesis of chronic airway diseases.Epithelial sodium channels (ENaC) and cystic fibrosis transmembrane conductance regulator (CFTR) are closely related to the mucociliary clearance.ENaC and CFTR jointly adjust the water layer of mucus, which affects the airway cilia clearance ability.Specific antagonists or activating agents of ENaC and CFTR could be novel pharmaceutical interventions for the prevention and treatment of asthma as well as other chronic airway diseases.

  10. Co-occurrence of point mutations in the voltage-gated sodium channel of pyrethroid-resistant Aedes aegypti populations in Myanmar.

    Directory of Open Access Journals (Sweden)

    Hitoshi Kawada

    Full Text Available BACKGROUND: Single amino acid substitutions in the voltage-gated sodium channel associated with pyrethroid resistance constitute one of the main causative factors of knockdown resistance in insects. The kdr gene has been observed in several mosquito species; however, point mutations in the para gene of Aedes aegypti populations in Myanmar have not been fully characterized. The aim of the present study was to determine the types and frequencies of mutations in the para gene of Aedes aegypti collected from used tires in Yangon City, Myanmar. METHODOLOGY/PRINCIPAL FINDINGS: We determined high pyrethroid resistance in Aedes aegypti larvae at all collection sites in Yangon City, by using a simplified knockdown bioassay. We showed that V1016G and S989P mutations were widely distributed, with high frequencies (84.4% and 78.8%, respectively. By contrast, we were unable to detect I1011M (or I1011V or L1014F mutations. F1534C mutations were also widely distributed, but with a lower frequency than the V1016G mutation (21.2%. High percentage of co-occurrence of the homozygous V1016G/S989P mutations was detected (65.7%. Additionally, co-occurrence of homozygous V1016G/F1534C mutations (2.9% and homozygous V1016G/F1534C/S989P mutations (0.98% were detected in the present study. CONCLUSIONS/SIGNIFICANCE: Pyrethroid insecticides were first used for malaria control in 1992, and have since been constantly used in Myanmar. This intensive use may explain the strong selection pressure toward Aedes aegypti, because this mosquito is generally a domestic and endophagic species with a preference for indoor breeding. Extensive use of DDT for malaria control before the use of this chemical was banned may also explain the development of pyrethroid resistance in Aedes aegypti.

  11. Discovery of Point Mutations in the Voltage-Gated Sodium Channel from African Aedes aegypti Populations: Potential Phylogenetic Reasons for Gene Introgression

    Science.gov (United States)

    Muranami, Yuto; Kawashima, Emiko; Osei, Joseph H. N.; Sakyi, Kojo Yirenkyi; Dadzie, Samuel; de Souza, Dziedzom K.; Appawu, Maxwell; Ohta, Nobuo; Minakawa, Noboru

    2016-01-01

    Background Yellow fever is endemic in some countries in Africa, and Aedes aegpyti is one of the most important vectors implicated in the outbreak. The mapping of the nation-wide distribution and the detection of insecticide resistance of vector mosquitoes will provide the beneficial information for forecasting of dengue and yellow fever outbreaks and effective control measures. Methodology/Principal Findings High resistance to DDT was observed in all mosquito colonies collected in Ghana. The resistance and the possible existence of resistance or tolerance to permethrin were suspected in some colonies. High frequencies of point mutations at the voltage-gated sodium channel (F1534C) and one heterozygote of the other mutation (V1016I) were detected, and this is the first detection on the African continent. The frequency of F1534C allele and the ratio of F1534C homozygotes in Ae. aegypti aegypti (Aaa) were significantly higher than those in Ae. aegypti formosus (Aaf). We could detect the two types of introns between exon 20 and 21, and the F1534C mutations were strongly linked with one type of intron, which was commonly found in South East Asian and South and Central American countries, suggesting the possibility that this mutation was introduced from other continents or convergently selected after the introgression of Aaa genes from the above area. Conclusions/Significance The worldwide eradication programs in 1940s and 1950s might have caused high selection pressure on the mosquito populations and expanded the distribution of insecticide-resistant Ae. aegypti populations. Selection of the F1534C point mutation could be hypothesized to have taken place during this period. The selection of the resistant population of Ae. aegypti with the point mutation of F1534C, and the worldwide transportation of vector mosquitoes in accordance with human activity such as trading of used tires, might result in the widespread distribution of F1534C point mutation in tropical countries

  12. Adsorption of charged protein residues on an inorganic nanosheet: Computer simulation of LDH interaction with ion channel

    Science.gov (United States)

    Tsukanov, Alexey A.; Psakhie, Sergey G.

    2016-08-01

    Quasi-two-dimensional and hybrid nanomaterials based on layered double hydroxides (LDH), cationic clays, layered oxyhydroxides and hydroxides of metals possess large specific surface area and strong electrostatic properties with permanent or pH-dependent electric charge. Such nanomaterials may impact cellular electrostatics, changing the ion balance, pH and membrane potential. Selective ion adsorption/exchange may alter the transmembrane electrochemical gradient, disrupting potential-dependent cellular processes. Cellular proteins as a rule have charged residues which can be effectively adsorbed on the surface of layered hydroxide based nanomaterials. The aim of this study is to attempt to shed some light on the possibility and mechanisms of protein "adhesion" an LDH nanosheet and to propose a new direction in anticancer medicine, based on physical impact and strong electrostatics. An unbiased molecular dynamics simulation was performed and the combined process free energy estimation (COPFEE) approach was used.

  13. Modulation of mononuclear phagocyte inflammatory response by liposome-encapsulated voltage gated sodium channel inhibitor ameliorates myocardial ischemia/reperfusion injury in rats.

    Directory of Open Access Journals (Sweden)

    Xin Zhou

    Full Text Available BACKGROUND: Emerging evidence shows that anti-inflammatory strategies targeting inflammatory monocyte subset could reduce excessive inflammation and improve cardiovascular outcomes. Functional expression of voltage-gated sodium channels (VGSCs have been demonstrated in monocytes and macrophages. We hypothesized that mononuclear phagocyte VGSCs are a target for monocyte/macrophage phenotypic switch, and liposome mediated inhibition of mononuclear phagocyte VGSC may attenuate myocardial ischemia/reperfusion (I/R injury and improve post-infarction left ventricular remodeling. METHODOLOGY/PRINCIPAL FINDINGS: Thin film dispersion method was used to prepare phenytoin (PHT, a non-selective VGSC inhibitor entrapped liposomes. Pharmacokinetic study revealed that the distribution and elimination half-life of PHT entrapped liposomes were shorter than those of free PHT, indicating a rapid uptake by mononuclear phagocytes after intravenous injection. In rat peritoneal macrophages, several VGSC α subunits (NaV1.1, NaV1.3, NaV1.4, NaV1.5, NaV1.6, NaV1.7, NaVX, Scn1b, Scn3b and Scn4b and β subunits were expressed at mRNA level, and PHT could suppress lipopolysaccharide induced M1 polarization (decreased TNF-α and CCL5 expression and facilitate interleukin-4 induced M2 polarization (increased Arg1 and TGF-β1 expression. In vivo study using rat model of myocardial I/R injury, demonstrated that PHT entrapped liposome could partially suppress I/R injury induced CD43+ inflammatory monocyte expansion, along with decreased infarct size and left ventricular fibrosis. Transthoracic echocardiography and invasive hemodynamic analysis revealed that PHT entrapped liposome treatment could attenuate left ventricular structural and functional remodeling, as shown by increased ejection fraction, reduced end-systolic and end-diastolic volume, as well as an amelioration of left ventricular systolic (+dP/dt max and diastolic (-dP/dt min functions. CONCLUSIONS/SIGNIFICANCE: Our

  14. Validation of a CFD model simulating charge and discharge of a small heat storage test module based on a sodium acetate water mixture

    DEFF Research Database (Denmark)

    Dannemand, Mark; Fan, Jianhua; Furbo, Simon;

    2014-01-01

    Computational Fluid Dynamics (CFD) model. The CFD calculated temperatures are compared to measured temperatures internally in the box to validate the CFD model. Four cases are investigated; heating the test module with the sodium acetate water mixture in solid phase from ambient temperature to 52˚C; heating the...... the crystallization, ending at ambient temperature with the sodium acetate water mixture in solid phase. Comparisons have shown reasonable good agreement between experimental measurements and theoretical simulation results for the investigated scenarios....

  15. Firewall function of the endothelial glycocalyx in the regulation of sodium homeostasis.

    Science.gov (United States)

    Korte, Stefanie; Wiesinger, Anne; Straeter, Alexandra S; Peters, Wladimir; Oberleithner, Hans; Kusche-Vihrog, Kristina

    2012-02-01

    Plasma sodium, slightly above normal and in presence of aldosterone, stiffens vascular endothelium and reduces nitric oxide release with the consequence of endothelial dysfunction. This process is mediated by epithelial sodium channels (ENaC) and, most likely, the endothelial Na(+)/K(+)-ATPase. Both, ENaC and Na(+)/K(+)-ATPase, are located in the plasma membrane of endothelial cells and embedded in the endothelial glycocalyx (eGC). This negatively charged biopolymer is directly exposed to the blood stream and selectively buffers sodium ions. We hypothesize that the glycocalyx could interfere with endothelial sodium transport when extracellular sodium varies in the physiological range. Therefore, we modeled the endothelial cell as a pump-leak system measuring changes of intracellular sodium in cultured human endothelial cells. Experiments were performed under low/high extracellular sodium conditions before and after enzymatic eGC removal, and with inhibition of Na(+)/K(+)-ATPase and ENaC, respectively. Three major observations were made: (1) eGC removal by heparinase treatment facilitates sodium to enter/exit the endothelial cells. (2) The direction of net sodium movement across the endothelial plasma membrane depends on the concentration of extracellular sodium which regulates both the Na(+)/K(+)-ATPase and ENaC activity. (3) Removal of eGC and inhibition of sodium transport modify the electrical resistance of endothelial cells. We conclude that the eGC serves as a potential "firewall" preventing uncontrolled access of sodium to the pump-leak system of the endothelial cell. After eGC removal, sodium access to the system is facilitated. Thus the pump-leak system could be regulated by ambient sodium and control vascular permeability in pathophysiological conditions. PMID:22057584

  16. Caracterización del canal epitelial de sodio en sinciciotrofoblasto de placenta humana preeclamptica Characterization of the epithelial sodium channel in human pre-eclampsia syncytiotrophoblast

    Directory of Open Access Journals (Sweden)

    Silvana del Mónaco

    2006-02-01

    epithelial Na channel (ENaC in placental tissue from normal and pre-eclamptic women and in BeWo cell, a model of a human SCT. Changes in the expression of these proteins during sodium transport across the placenta may be related to the pathogeny of pre-eclampsia. The role that ENaC and Na+ transport deregulation play on human placental tissues still remains unknown although in aldosterone-responsive epithelial cells (kidney, colon, abnormalities upregulating its activity lead to increased Na+ uptake and hypertension (i.e. Liddle´s syndrome whereas a diminished channel activity can result in the pseudohypoaldosteronisn syndrome with salt loss and hypotension. Our results show that ENaC is expressed in the apical membrane of normal syncytiotrophoblast. The amplified fragment of a-ENaC was cloned and sequenced having a 100% identity with the sequence of a-ENaC obtained from GenBankTM (SCNN1A, accession number Z92981. We found that the transcription of the a-ENaC mRNA was not detectable in preeclamptic placentas and the protein was not observed with immunohistochemistry staining, probably indicating a low protein expression level. In BeWo cells ENac was found and its expression is regulated by aldosterone, vasopressin, progesterone and estradiol. With patch clamp techniques we studied the currents trough ENaC channels in Bewo cells. We observed currents that were blocked by 10 µM amiloride in cells incubated in 100 nM aldosterone for 12 hs. The amplitude of this current was 20-fold the basal current, a reversal potential of 3 mV and a conductance of 127 ± 26 pS/pF with pulses between -60 and -140 mV. These characteristics are similar to those reported in ENaC channels in several tissues. Although their roles in placenta are still poorly understood, the differences in the expression of ENaC in pre-eclamptic placentas may have consequences for ion transport and these data could lead to future studies concerning the mechanism involved in the pathophysiology of pre-eclampsia.

  17. Interaction of Tarantula Venom Peptide ProTx-II with Lipid Membranes Is a Prerequisite for Its Inhibition of Human Voltage-gated Sodium Channel NaV1.7.

    Science.gov (United States)

    Henriques, Sónia Troeira; Deplazes, Evelyne; Lawrence, Nicole; Cheneval, Olivier; Chaousis, Stephanie; Inserra, Marco; Thongyoo, Panumart; King, Glenn F; Mark, Alan E; Vetter, Irina; Craik, David J; Schroeder, Christina I

    2016-08-12

    ProTx-II is a disulfide-rich peptide toxin from tarantula venom able to inhibit the human voltage-gated sodium channel 1.7 (hNaV1.7), a channel reported to be involved in nociception, and thus it might have potential as a pain therapeutic. ProTx-II acts by binding to the membrane-embedded voltage sensor domain of hNaV1.7, but the precise peptide channel-binding site and the importance of membrane binding on the inhibitory activity of ProTx-II remain unknown. In this study, we examined the structure and membrane-binding properties of ProTx-II and several analogues using NMR spectroscopy, surface plasmon resonance, fluorescence spectroscopy, and molecular dynamics simulations. Our results show a direct correlation between ProTx-II membrane binding affinity and its potency as an hNaV1.7 channel inhibitor. The data support a model whereby a hydrophobic patch on the ProTx-II surface anchors the molecule at the cell surface in a position that optimizes interaction of the peptide with the binding site on the voltage sensor domain. This is the first study to demonstrate that binding of ProTx-II to the lipid membrane is directly linked to its potency as an hNaV1.7 channel inhibitor. PMID:27311819

  18. Cloning and sequence analysis of para sodium channel cDNA fragment from silkworm, Bombyx mori%家蚕Para钠通道cDNA片段克隆与序列分析

    Institute of Scientific and Technical Information of China (English)

    何琳; 刘丽花; 汪洋

    2011-01-01

    Previous studies have revealed that a point mutation of a target gene is related to insecticide resistance to pyrethroids. The para sodium channel in the insect central nervous system is the target of pyrethroid insecticides. We used the RT-PCR method to clone the para sodium ion channel in the silkworm, Bombyx mori L. (GenBank No. EF521818).The full length of this cDNA fragment is 4 882 base pairs and its partial ORF is 3 986 bp translated into 1 328 amino acids. BLAST analysis demonstrated that the cloned cDNA fragment is virtually identical to the para sodium channel a subunit gene amplified from other insects. Amino acid homology of the cloned fragment with para sodium channel a subunit genes from Heliothis virescens Fabricius, Aedes aegypti L. , Blattella germanica L. , Drosophila melanogaster Meigen and Musca domestica L. was 95%, 82%, 80%, 79% and 77% respectively.%昆虫神经系统para型钠离子通道是拟除虫菊酯类杀虫剂的主要靶标,已有的研究表明钠离子通道基因发生点突变与昆虫对菊酯类杀虫剂的抗性密切相关.本文通过RT-PCR方法克隆获得了编码家蚕Bombyx mori L.钠离子通道的cDNA片段(GenBank No.EF521818),该片段全长4 882 bp,部分ORF包含3 986 bp核苷酸,翻译成1 328个氨基酸.蛋白序列分析表明,PCR扩增获得的家蚕钠离子通道eDNA片段所编码的氨基酸与其他昆虫的para型钠离子通道α亚基的氨基酸具有很高的同源相似性,与棉铃虫Heliothis virescens Fabricius、埃及伊蚊Aedes aegypti L.、德国小蠊Blattella germanica L.、果蝇Drosophila melanogaster Meigen和家蝇Musca domestica L.的相似性分别为95%、82%、80%、79%、77%.

  19. The 8πLP project at LNL. A detection system for light charged particles with deexcitation channel selection

    International Nuclear Information System (INIS)

    A 4π detection system sensitive to light charged particles is being developed at the Laboratori Nazionali di Legnaro (LNL) for the study of the reaction mechanisms produced in heavy-ion collisions at energies up to 20 AMeV. The 8πLP apparatus is a telescope assembly characterized by large solid angle (90% of 4π) and high granularity (262 modules). Particle identification at low energy is enhanced by combining ΔE-E, TOF and PSD techniques. Thresholds for particle identification range from 1 MeV for protons and 3 MeV for alpha particles to about 2-3 AMeV for C ions. The system is fully operational for experiments

  20. Coevolution of the Ile1,016 and Cys1,534 Mutations in the Voltage Gated Sodium Channel Gene of Aedes aegypti in Mexico.

    Directory of Open Access Journals (Sweden)

    Farah Z Vera-Maloof

    2015-12-01

    Full Text Available Worldwide the mosquito Aedes aegypti (L. is the principal urban vector of dengue viruses. Currently 2.5 billion people are at risk for infection and reduction of Ae. aegypti populations is the most effective means to reduce the risk of transmission. Pyrethroids are used extensively for adult mosquito control, especially during dengue outbreaks. Pyrethroids promote activation and prolong the activation of the voltage gated sodium channel protein (VGSC by interacting with two distinct pyrethroid receptor sites [1], formed by the interfaces of the transmembrane helix subunit 6 (S6 of domains II and III. Mutations of S6 in domains II and III synergize so that double mutants have higher pyrethroid resistance than mutants in either domain alone. Computer models predict an allosteric interaction between mutations in the two domains. In Ae. aegypti, a Ile1,016 mutation in the S6 of domain II was discovered in 2006 and found to be associated with pyrethroid resistance in field populations in Mexico. In 2010 a second mutation, Cys1,534 in the S6 of domain III was discovered and also found to be associated with pyrethroid resistance and correlated with the frequency of Ile1,016.A linkage disequilibrium analysis was performed on Ile1,016 and Cys1,534 in Ae. aegypti collected in Mexico from 2000-2012 to test for statistical associations between S6 in domains II and III in natural populations. We estimated the frequency of the four dilocus haplotypes in 1,016 and 1,534: Val1,016/Phe1,534 (susceptible, Val1,016/Cys1,534, Ile1,016/Phe1,534, and Ile1,016/Cys1,534 (resistant. The susceptible Val1,016/Phe1,534 haplotype went from near fixation to extinction and the resistant Ile1,016/Cys1,534 haplotype increased in all collections from a frequency close to zero to frequencies ranging from 0.5-0.9. The Val1,016/Cys1,534 haplotype increased in all collections until 2008 after which it began to decline as Ile1,016/Cys1,534 increased. However, the Ile1,016/Phe1

  1. Cardiac sodium channelopathies

    NARCIS (Netherlands)

    A.S. Amin; A. Asghari-Roodsari; H.L. Tan

    2010-01-01

    Cardiac sodium channel are protein complexes that are expressed in the sarcolemma of cardiomyocytes to carry a large inward depolarizing current (I-Na) during phase 0 of the cardiac action potential. The importance of I-Na for normal cardiac electrical activity is reflected by the high incidence of

  2. 作用钠离子通道海洋生物毒素的研究及检测进展%Advancement in researches of impact of marine biotoxins on sodium channel

    Institute of Scientific and Technical Information of China (English)

    袁建辉; 誉倩文; 杨慧; 唐焕文

    2011-01-01

    离子通道类毒素是一类特异性作用于离子通道的神经毒素,而海洋生物毒素中有许多毒素都是通过作用于Na+通道蛋白来影响与受体有关的一系列细胞调控活动,它们以其独特的化学结构和毒理特性,将成为21世纪研究与开发海洋资源的重要组成部分.本文就海洋生物中几种主要的Na+通道受体神经毒素及其检测技术做一概述,为其研究提供科学参考.%Ion channels toxins are a class of neurotoxins acting on ion channels,and marine biotoxins,there are many toxins affect a series of cellular regulation of activities by effect on the Sodium Channel receptor. Their unique chemical structure and toxicological properties will be an important component of marine resources in the 21st century. In this paper, in order to provide a reference for the related research,several major oceans Na+ channel receptor neurotoxins and their detection technologies are reviewed.

  3. TRPM8 and Nav1.8 sodium channels are required for transthyretin-induced calcium influx in growth cones of small-diameter TrkA-positive sensory neurons

    Directory of Open Access Journals (Sweden)

    Vincent Adele J

    2011-03-01

    Full Text Available Abstract Background Familial amyloidotic polyneuropathy (FAP is a peripheral neuropathy caused by the extracellular accumulation and deposition of insoluble transthyretin (TTR aggregates. However the molecular mechanism that underlies TTR toxicity in peripheral nerves is unclear. Previous studies have suggested that amyloidogenic proteins can aggregate into oligomers which disrupt intracellular calcium homeostasis by increasing the permeability of the plasma membrane to extracellular calcium. The aim of the present study was to examine the effect of TTR on calcium influx in dorsal root ganglion neurons. Results Levels of intracellular cytosolic calcium were monitored in dorsal root ganglion (DRG neurons isolated from embryonic rats using the calcium-sensitive fluorescent indicator Fluo4. An amyloidogenic mutant form of TTR, L55P, induced calcium influx into the growth cones of DRG neurons, whereas wild-type TTR had no significant effect. Atomic force microscopy and dynamic light scattering studies confirmed that the L55P TTR contained oligomeric species of TTR. The effect of L55P TTR was decreased by blockers of voltage-gated calcium channels (VGCC, as well as by blockers of Nav1.8 voltage-gated sodium channels and transient receptor potential M8 (TRPM8 channels. siRNA knockdown of TRPM8 channels using three different TRPM8 siRNAs strongly inhibited calcium influx in DRG growth cones. Conclusions These data suggest that activation of TRPM8 channels triggers the activation of Nav1.8 channels which leads to calcium influx through VGCC. We suggest that TTR-induced calcium influx into DRG neurons may contribute to the pathophysiology of FAP. Furthermore, we speculate that similar mechanisms may mediate the toxic effects of other amyloidogenic proteins such as the β-amyloid protein of Alzheimer's disease.

  4. Ionic Coulomb Blockade and Resonant Conduction in Biological Ion Channels

    CERN Document Server

    Kaufman, I Kh; Eisenberg, R S

    2014-01-01

    The conduction and selectivity of calcium/sodium ion channels are described in terms of ionic Coulomb blockade, a phenomenon based on charge discreteness and an electrostatic model of an ion channel. This novel approach provides a unified explanation of numerous observed and modelled conductance and selectivity phenomena, including the anomalous mole fraction effect and discrete conduction bands. Ionic Coulomb blockade and resonant conduction are similar to electronic Coulomb blockade and resonant tunnelling in quantum dots. The model is equally applicable to other nanopores.

  5. Sodium Oxybate

    Science.gov (United States)

    Sodium oxybate is used to prevent attacks of cataplexy (episodes of muscle weakness that begin suddenly and ... urge to sleep during daily activities, and cataplexy). Sodium oxybate is in a class of medications called ...

  6. Sodium Test

    Science.gov (United States)

    ... be limited. Home Visit Global Sites Search Help? Sodium Share this page: Was this page helpful? Also known as: Na Formal name: Sodium Related tests: Chloride , Bicarbonate , Potassium , Electrolytes , Osmolality , Basic ...

  7. Sodium Phosphate

    Science.gov (United States)

    Sodium phosphate is used in adults 18 years of age or older to empty the colon (large intestine, bowel) ... view of the walls of the colon. Sodium phosphate is in a class of medications called saline ...

  8. [Transport of large organic ions through syringomycin channels in the membranes containing dipole modifiers].

    Science.gov (United States)

    Efimova, S S; Ostroumova, O S; Malev, V V; Shchagina, L V

    2011-01-01

    The effect of the membrane dipole potential (Phid) on a conductance and a steady-state number of functioning channels formed by cyclic lipodepsipeptide syringomycin E (SRE) in bilayer lipid membranes made from phosphocholine and bathed in 0.4 M solution of sodium salts of aspartate, gluconate and chloride was shown. The magnitude of Phid was varied with the introduction to membrane bathing solutions of phloretin, which reduces the Phid, and RH 421, increasing the Phid. It was established that in all studied systems the increase in the membrane dipole potential cause a decrease in the steady-state number of open channels. In the systems containing sodium salts of aspartate (Asp) or gluconate (Glc), changes in the number of functioning channels are in an order of magnitude smaller than in systems containing sodium chloride. At the same time, the conductance (g) of single SRE-channels on the membranes bathed in NaCI solution increases with the increase in Phid, and in the systems containing NaAsp or NaGlc the conductance of single channels does not depend on the Phid. The latter is due to the lack of cation/anion selectivity of the SRE-channels in these systems. The different channel-forming activity of SRE in the experimental systems is defined by the gating charge of the channel and the partition coefficient of the dipole modifiers between the lipid and aqueous phases.

  9. Design of Low-Noise Output Amplifiers for P-channel Charge-Coupled Devices Fabricated on High-Resistivity Silicon

    Energy Technology Data Exchange (ETDEWEB)

    Haque, S; Frost, F Dion R.; Groulx, R; Holland, S E; Karcher, A; Kolbe, W F; Roe, N A; Wang, G; Yu, Y

    2011-12-22

    We describe the design and optimization of low-noise, single-stage output amplifiers for p-channel charge-coupled devices (CCDs) used for scientific applications in astronomy and other fields. The CCDs are fabricated on high-resistivity, 4000–5000 -cm, n-type silicon substrates. Single-stage amplifiers with different output structure designs and technologies have been characterized. The standard output amplifier is designed with an n{sup +} polysilicon gate that has a metal connection to the sense node. In an effort to lower the output amplifier readout noise by minimizing the capacitance seen at the sense node, buried-contact technology has been investigated. In this case, the output transistor has a p{sup +} polysilicon gate that connects directly to the p{sup +} sense node. Output structures with buried-contact areas as small as 2 μm × 2 μm are characterized. In addition, the geometry of the source-follower transistor was varied, and we report test results on the conversion gain and noise of the various amplifier structures. By use of buried-contact technology, better amplifier geometry, optimization of the amplifier biases and improvements in the test electronics design, we obtain a 45% reduction in noise, corresponding to 1.7 e{sup -} rms at 70 kpixels/sec.

  10. Effects on the sodium channel of some new cardiotonic drugs: the 4-, 5-, and 6-pyridyl-2(1H)-quinolone derivatives

    Energy Technology Data Exchange (ETDEWEB)

    Grima, M.; Beguin, M.F.; Millanvoye-Van Brussel, E.M.; Decker, N.; Schwartz, J.

    1988-09-01

    To study the action of some new cardiotonic drugs, the 4-, 5-, and 6-pyridyl-2(1H)-quinolone series, on the fast Na+ channel, we compared the effects of eight compounds of this series and milrinone on /sup 22/Na uptake in rat brain synaptosomes and in rat heart muscle cells in culture. The action of tetrodotoxin, a specific Na+ channel blocker, on the positive inotropic effect of these compounds on guinea pig atria was also examined. The new positive inotropic agents enhance /sup 22/Na uptake in synaptosomes in a dose-dependent manner. The activities, expressed as percentage of the maximum activity of protoveratrine B, a classic Na+ channel agonist, reached 70% for milrinone, 60% for compound 7, 57% for compound 6, and less than 50% for the other drugs. For compound 8, but not for milrinone, it was possible to observe a stimulatory effect of the /sup 22/Na uptake on heart muscle cells in culture. Tetrodotoxin (1 and 100 microM) inhibited the stimulatory effects of the inotropic drugs on both preparations. The positive inotropic activities of protoveratrine B, milrinone, and compounds 5 and 8, in guinea pig atria, were inhibited by tetrodotoxin. The affinity and the activity of the other compounds were unchanged in the presence of tetrodotoxin. Our results showed that the stimulation of Na+ influx through the fast Na+ channel might represent a part of the mechanism of action of the inotropic effect of some new cardiotonic drugs.

  11. Severe Salt-Losing Syndrome and Hyperkalemia Induced by Adult Nephron-Specific Knockout of the Epithelial Sodium Channel α-Subunit

    DEFF Research Database (Denmark)

    2015-01-01

    is neonatally lethal in mice. We generated adult inducible nephron-specific αENaC-knockout mice (Scnn1a(Pax8/LC1)) that exhibit hyperkalemia and body weight loss when kept on a regular-salt diet, thus mimicking PHA-1. Compared with control mice fed a regular-salt diet, knockout mice fed a regular-salt diet...... exhibited downregulated expression and phosphorylation of NCC protein, despite high plasma aldosterone levels. In knockout mice fed a high-sodium and reduced-potassium diet (rescue diet), although plasma aldosterone levels remained significantly increased, NCC expression returned to control levels, and body...

  12. Identification of Amino Acid Residues in Fibroblast Growth Factor 14 (FGF14) Required for Structure-Function Interactions with Voltage-gated Sodium Channel Nav1.6.

    Science.gov (United States)

    Ali, Syed R; Singh, Aditya K; Laezza, Fernanda

    2016-05-20

    The voltage-gated Na(+) (Nav) channel provides the basis for electrical excitability in the brain. This channel is regulated by a number of accessory proteins including fibroblast growth factor 14 (FGF14), a member of the intracellular FGF family. In addition to forming homodimers, FGF14 binds directly to the Nav1.6 channel C-tail, regulating channel gating and expression, properties that are required for intrinsic excitability in neurons. Seeking amino acid residues with unique roles at the protein-protein interaction interface (PPI) of FGF14·Nav1.6, we engineered model-guided mutations of FGF14 and validated their impact on the FGF14·Nav1.6 complex and the FGF14:FGF14 dimer formation using a luciferase assay. Divergence was found in the β-9 sheet of FGF14 where an alanine (Ala) mutation of Val-160 impaired binding to Nav1.6 but had no effect on FGF14:FGF14 dimer formation. Additional analysis revealed also a key role of residues Lys-74/Ile-76 at the N-terminal of FGF14 in the FGF14·Nav1.6 complex and FGF14:FGF14 dimer formation. Using whole-cell patch clamp electrophysiology, we demonstrated that either the FGF14(V160A) or the FGF14(K74A/I76A) mutation was sufficient to abolish the FGF14-dependent regulation of peak transient Na(+) currents and the voltage-dependent activation and steady-state inactivation of Nav1.6; but only V160A with a concomitant alanine mutation at Tyr-158 could impede FGF14-dependent modulation of the channel fast inactivation. Intrinsic fluorescence spectroscopy of purified proteins confirmed a stronger binding reduction of FGF14(V160A) to the Nav1.6 C-tail compared with FGF14(K74A/I76A) Altogether these studies indicate that the β-9 sheet and the N terminus of FGF14 are well positioned targets for drug development of PPI-based allosteric modulators of Nav channels. PMID:26994141

  13. Regulación por proteasas del canal de sodio sensible al amiloride (ENaC Amiloride sensitive sodium channels (ENaC and their regulation by proteases

    Directory of Open Access Journals (Sweden)

    Luciano Galizia

    2011-04-01

    Full Text Available El ENaC es un canal que permite el movimiento de Na+ desde el líquido luminal hacia las células en numerosos epitelios reabsortivos y también en otros tejidos como la placenta. ENaC juega un papel crucial en la homeostasis de los electrolitos y volumen de líquido extracelular. Es regulado por numerosas hormonas, incluyendo la aldosterona y bloqueado por el diurético amiloride. El ENaC está formado por tres subunidades homólogas α, β y γ que forman el poro por el cual se mueven los iones Na+. Dos factores regulan la actividad del ENaC. 1 el número de canales insertos en la membrana celular y 2 la probabilidad de apertura o tiempo en que se encuentra abierto el canal. El número de canales es el resultado de un balance entre su síntesis y degradación. La probabilidad de apertura depende de la proteólisis de zonas específicas de las subunidades α y γ por múltiples proteasas dentro de la célula y en el espacio extracelular. Entre las proteasas más estudiadas se encuentran la furina, prostasina, elastasa, plasmina y tripsina. Existen sustancias endógenas que bloquean la actividad de estas proteasas como la aprotinina, la bikunina y la nexina-1 y la expresión de las proteasas y sus inhibidores es regulada a su vez por la aldosterona, la tasa de movimiento de Na y el TFGβ. En este trabajo presentamos algunos ejemplos de esta regulación y su potencial papel en condiciones normales y en ciertas enfermedades como la fibrosis quística, renales e hipertensión.ENaC is a channel that mediates entry of Na+ from the luminal fluid into the cells in many reabsorbing epithelia and it is also expressed in human placenta. ENaC is crucial in the control of electrolyte and extracellular volume homeostasis. ENaC is regulated by several hormones, including aldosterone and blocked by amiloride and its analogs. ENaC channels are composed by three homologous subunits, α, β and γ that form the pore where Na ions are transported. Two factors

  14. Functionally distinct sodium channels in ventricular epicardial and endocardial cells contribute to a greater sensitivity of the epicardium to electrical depression

    OpenAIRE

    Cordeiro, J. M.; Mazza, M.; Goodrow, R.; Ulahannan, N.; Antzelevitch, C; DI DIEGO, J.M.

    2008-01-01

    A greater depression of the action potential (AP) of the ventricular epicardium (Epi) versus endocardium (Endo) is readily observed in experimental models of acute ischemia and Brugada syndrome. Endo and Epi differences in transient outward K+ current and/or ATP-sensitive K+ channel current are believed to contribute to the differential response. The present study tested the hypothesis that the greater sensitivity of Epi is due in part to its functionally distinct early fast Na+ current (INa)...

  15. Effects of L-type Ca2+ channel antagonists on in vitro excystment of Paragonimus ohirai metacercariae induced by sodium cholate.

    Science.gov (United States)

    Ikeda, Teruaki

    2006-09-01

    The inhibitory effects of L-type Ca2+ channel antagonists on Na cholate-induced in vitro excystment (CIIE) of Paragonimus ohirai metacercariae were studied. At concentrations of 10 microM, nicardipine and nimodipine inhibited CIIE completely and by approximately 92%, respectively. Nitrendipine and (+/-)-verapamil inhibited CIIE by about one half and one third, respectively. Nifedipine and diltiazem did not inhibit CIIE significantly. At higher concentrations, nitrendipine at 20 microM completely inhibited CIIE, and (+/-)-verapamil at 40 microM inhibited CIIE by 93%. Nifedipine and diltiazem inhibited CIIE only slightly and little, respectively, even at 40 microM. Complete inhibition by nicardipine at 10 microM required preincubation of metacercariae with the antagonist for 15 min. The inhibitory effects of nicardipine and nimodipine were reversible, and most of the nimodipine-treated metacercariae could excyst within 1 h after being washed, but the nicardipine-treated ones started to excyst 1 h after washing. Nicardipine suppressed the active movement of encysted juveniles evoked by Na cholate, whereas nimodipine did not suppress this significantly. These results suggested that L-type Ca2+ channels appeared to be involved in CIIE of P. ohirai metacercariae and that the inhibitory effect of the channels was due primarily to factors other than the inhibition of muscular activity, probably involving the secretion and release of enzymes lytic against the metacercarial cyst wall.

  16. Fast Nongenomic Effect of Aldosterone on the Volume of Principal Cells in Collecting Tube and Genetic Heterogeneity of Epithelial Sodium Channel in the Postnatal Ontogenesis of Rat Kidney.

    Science.gov (United States)

    Logvinenko, N S; Gerbek, Yu E; Solenov, E I; Ivanova, L N

    2016-03-01

    The effects of amiloride, epithelial sodium pump inhibitor, on the fast nongenomic effect of aldosterone in principal cells of an isolated segment of the distal portion of renal collecting tubes were studied in 10-day-old and adult rats. Fluorescent staining with Calcein AM showed various effects of amiloride (10(-5) M) on the stabilizing effect of aldosterone (10 nM) in hypotonic shock (280/140 mOsm/kg). Amiloride attenuated by 30% the effect of aldosterone on the amplitude of principal cell swelling in adult animals and almost completely abolished this effect in 10-day rats (p<0.05). These age-specific differences in the contribution of the distal portion of the collecting tube to the nongenomic effect of aldosterone did not depend on genetic heterogeneity of its α-subunit. PMID:27021081

  17. Molecular dissection of the contribution of negatively and positively charged residues in S2, S3, and S4 to the final membrane topology of the voltage sensor in the K+ channel, KAT1.

    Science.gov (United States)

    Sato, Yoko; Sakaguchi, Masao; Goshima, Shinobu; Nakamura, Tatsunosuke; Uozumi, Nobuyuki

    2003-04-11

    Voltage-dependent ion channels control changes in ion permeability in response to membrane potential changes. The voltage sensor in channel proteins consists of the highly positively charged segment, S4, and the negatively charged segments, S2 and S3. The process involved in the integration of the protein into the membrane remains to be elucidated. In this study, we used in vitro translation and translocation experiments to evaluate interactions between residues in the voltage sensor of a hyperpolarization-activated potassium channel, KAT1, and their effect on the final topology in the endoplasmic reticulum (ER) membrane. A D95V mutation in S2 showed less S3-S4 integration into the membrane, whereas a D105V mutation allowed S4 to be released into the ER lumen. These results indicate that Asp(95) assists in the membrane insertion of S3-S4 and that Asp(105) helps in preventing S4 from being releasing into the ER lumen. The charge reversal mutation, R171D, in S4 rescued the D105R mutation and prevented S4 release into the ER lumen. A series of constructs containing different C-terminal truncations of S4 showed that Arg(174) was required for correct integration of S3 and S4 into the membrane. Interactions between Asp(105) and Arg(171) and between negative residues in S2 or S3 and Arg(174) may be formed transiently during membrane integration. These data clarify the role of charged residues in S2, S3, and S4 and identify posttranslational electrostatic interactions between charged residues that are required to achieve the correct voltage sensor topology in the ER membrane.

  18. NMR analysis of interaction of LqhalphaIT scorpion toxin with a peptide corresponding to the D4/S3-S4 loop of insect para voltage-gated sodium channel.

    Science.gov (United States)

    Schnur, Einat; Turkov, Michael; Kahn, Roy; Gordon, Dalia; Gurevitz, Michael; Anglister, Jacob

    2008-01-22

    Voltage-gated sodium channels (Navs) are large transmembrane proteins that initiate action potential in electrically excitable cells. This central role in the nervous system has made them a primary target for a large number of neurotoxins. Scorpion alpha-neurotoxins bind to Navs with high affinity and slow their inactivation, causing a prolonged action potential. Despite the similarity in their mode of action and three-dimensional structure, alpha-toxins exhibit great variations in selectivity toward insect and mammalian Navs, suggesting differences in the binding surfaces of the toxins and the channels. The scorpion alpha-toxin binding site, termed neurotoxin receptor site 3, has been shown to involve the extracellular S3-S4 loop in domain 4 of the alpha-subunit of voltage-gated sodium channels (D4/S3-S4). In this study, the binding site for peptides corresponding to the D4/S3-S4 loop of the para insect Nav was mapped on the highly insecticidal alpha-neurotoxin, LqhalphaIT, from the scorpion Leiurus quinquestriatus hebraeus, by following changes in the toxin amide 1H and 15N chemical shifts upon binding. This analysis suggests that the five-residue turn (residues LqK8-LqC12) of LqhalphaIT and those residues in its vicinity interact with the D4/S3-S4 loop of Nav. Residues LqR18, LqW38, and LqA39 could also form a patch contributing to the interaction with D4/S3-S4. Moreover, a new bioactive residue, LqV13, was identified as being important for Nav binding and specifically for the interaction with the D4/S3-S4 loop. The contribution of LqV13 to NaV binding was further verified by mutagenesis. Future studies involving other extracellular regions of Navs are required for further characterization of the structure of the LqhalphaIT-Navs binding site.

  19. Hidden Sodium

    Centers for Disease Control (CDC) Podcasts

    2013-03-04

    In this podcast, learn about reducing sodium intake by knowing what to eat and the main sources of sodium in the diet. It's important for a healthy lifestyle.  Created: 3/4/2013 by National Center for Chronic Disease Prevention and Health Promotion (NCCDPHP).   Date Released: 3/4/2013.

  20. Dietary sodium

    DEFF Research Database (Denmark)

    Graudal, Niels

    2015-01-01

    The 2013 Institute of Medicine (IOM) report "Sodium Intake in Populations: Assessment of Evidence" did not support the current recommendations of the IOM and the American Heart Association (AHA) to reduce daily dietary sodium intake to below 2,300 mg. The report concluded that the population......-based health outcome evidence was not sufficient to define a safe upper intake level for sodium. Recent studies have extended this conclusion to show that a sodium intake below 2,300 mg/day is associated with increased mortality. In spite of this increasing body of evidence, the AHA, Centers for Disease...... Control (CDC), other public health advisory bodies, and major medical journals have continued to support the current policy of reducing dietary sodium....

  1. Novel residues lining the CFTR chloride channel pore identified by functional modification of introduced cysteines.

    Science.gov (United States)

    Fatehi, Mohammad; Linsdell, Paul

    2009-04-01

    Substituted cysteine accessibility mutagenesis (SCAM) has been used widely to identify pore-lining amino acid side chains in ion channel proteins. However, functional effects on permeation and gating can be difficult to separate, leading to uncertainty concerning the location of reactive cysteine side chains. We have combined SCAM with investigation of the charge-dependent effects of methanethiosulfonate (MTS) reagents on the functional permeation properties of cystic fibrosis transmembrane conductance regulator (CFTR) Cl(-) channels. We find that cysteines substituted for seven out of 21 continuous amino acids in the eleventh and twelfth transmembrane (TM) regions can be modified by external application of positively charged [2-(trimethylammonium)ethyl] MTS bromide (MTSET) and negatively charged sodium [2-sulfonatoethyl] MTS (MTSES). Modification of these cysteines leads to changes in the open channel current-voltage relationship at both the macroscopic and single-channel current levels that reflect specific, charge-dependent effects on the rate of Cl(-) permeation through the channel from the external solution. This approach therefore identifies amino acid side chains that lie within the permeation pathway. Cysteine mutagenesis of pore-lining residues also affects intrapore anion binding and anion selectivity, giving more information regarding the roles of these residues. Our results demonstrate a straightforward method of screening for pore-lining amino acids in ion channels. We suggest that TM11 contributes to the CFTR pore and that the extracellular loop between TMs 11 and 12 lies close to the outer mouth of the pore. PMID:19381710

  2. The Snake with the Scorpion’s Sting: Novel Three-Finger Toxin Sodium Channel Activators from the Venom of the Long-Glanded Blue Coral Snake (Calliophis bivirgatus)

    Science.gov (United States)

    Yang, Daryl C.; Deuis, Jennifer R.; Dashevsky, Daniel; Dobson, James; Jackson, Timothy N. W.; Brust, Andreas; Xie, Bing; Koludarov, Ivan; Debono, Jordan; Hendrikx, Iwan; Hodgson, Wayne C.; Josh, Peter; Nouwens, Amanda; Baillie, Gregory J.; Bruxner, Timothy J. C.; Alewood, Paul F.; Lim, Kelvin Kok Peng; Frank, Nathaniel; Vetter, Irina; Fry, Bryan G.

    2016-01-01

    Millions of years of evolution have fine-tuned the ability of venom peptides to rapidly incapacitate both prey and potential predators. Toxicofera reptiles are characterized by serous-secreting mandibular or maxillary glands with heightened levels of protein expression. These glands are the core anatomical components of the toxicoferan venom system, which exists in myriad points along an evolutionary continuum. Neofunctionalisation of toxins is facilitated by positive selection at functional hotspots on the ancestral protein and venom proteins have undergone dynamic diversification in helodermatid and varanid lizards as well as advanced snakes. A spectacular point on the venom system continuum is the long-glanded blue coral snake (Calliophis bivirgatus), a specialist feeder that preys on fast moving, venomous snakes which have both a high likelihood of prey escape but also represent significant danger to the predator itself. The maxillary venom glands of C. bivirgatus extend one quarter of the snake’s body length and nestle within the rib cavity. Despite the snake’s notoriety its venom has remained largely unstudied. Here we show that the venom uniquely produces spastic paralysis, in contrast to the flaccid paralysis typically produced by neurotoxic snake venoms. The toxin responsible, which we have called calliotoxin (δ-elapitoxin-Cb1a), is a three-finger toxin (3FTx). Calliotoxin shifts the voltage-dependence of NaV1.4 activation to more hyperpolarised potentials, inhibits inactivation, and produces large ramp currents, consistent with its profound effects on contractile force in an isolated skeletal muscle preparation. Voltage-gated sodium channels (NaV) are a particularly attractive pharmacological target as they are involved in almost all physiological processes including action potential generation and conduction. Accordingly, venom peptides that interfere with NaV function provide a key defensive and predatory advantage to a range of invertebrate

  3. Phospholipid membrane-interaction of a peptide from S4 segment of KvAP K(+) channel and the influence of the positive charges and an identified heptad repeat in its interaction with a S3 peptide.

    Science.gov (United States)

    Verma, Richa; Ghosh, Jimut Kanti

    2011-06-01

    In order to examine the ability of S3 and S4 segments of a Kv channel to interact with each other, two wild type short peptides derived from the S3 and S4 segments of KvAP channel were synthesized. Additionally, to evaluate the role of positive charges and an identified heptad repeat in the S4 segment, two S4 mutants of the same size as the S4 peptide, one with substitution of two leucine residues in the heptad repeat sequence by two alanine residues and in the other two arginine residues replaced by two glutamines residues were synthesized. Our results show that only the wild type S4 peptide, but not its mutants, self-assembled and permeabilized negatively charged phospholipid vesicles. The S3 peptide showed lesser affinity toward the same kind of lipid vesicles and localized onto its surface. However, the S3 peptide interacted only with S4 wild type peptide, but not with S4 mutants, and altered its localization onto the phospholipid membrane with increased resistance against the proteolytic enzyme, proteinase-k, in the presence of the S4 peptide. The results demonstrate that the selected, synthetic S3 and S4 segments possess the required amino acid sequences to interact with each other and show that the positive charges and the identified heptad repeat in S4 contribute to its assembly and interaction with S3 segment.

  4. Inhibition of Inactive States of Tetrodotoxin-Sensitive Sodium Channels Reduces Spontaneous Firing of C-Fiber Nociceptors and Produces Analgesia in Formalin and Complete Freund's Adjuvant Models of Pain.

    Directory of Open Access Journals (Sweden)

    David J Matson

    Full Text Available While genetic evidence shows that the Nav1.7 voltage-gated sodium ion channel is a key regulator of pain, it is unclear exactly how Nav1.7 governs neuronal firing and what biophysical, physiological, and distribution properties of a pharmacological Nav1.7 inhibitor are required to produce analgesia. Here we characterize a series of aminotriazine inhibitors of Nav1.7 in vitro and in rodent models of pain and test the effects of the previously reported "compound 52" aminotriazine inhibitor on the spiking properties of nociceptors in vivo. Multiple aminotriazines, including some with low terminal brain to plasma concentration ratios, showed analgesic efficacy in the formalin model of pain. Effective concentrations were consistent with the in vitro potency as measured on partially-inactivated Nav1.7 but were far below concentrations required to inhibit non-inactivated Nav1.7. Compound 52 also reversed thermal hyperalgesia in the complete Freund's adjuvant (CFA model of pain. To study neuronal mechanisms, electrophysiological recordings were made in vivo from single nociceptive fibers from the rat tibial nerve one day after CFA injection. Compound 52 reduced the spontaneous firing of C-fiber nociceptors from approximately 0.7 Hz to 0.2 Hz and decreased the number of action potentials evoked by suprathreshold tactile and heat stimuli. It did not, however, appreciably alter the C-fiber thresholds for response to tactile or thermal stimuli. Surprisingly, compound 52 did not affect spontaneous activity or evoked responses of Aδ-fiber nociceptors. Results suggest that inhibition of inactivated states of TTX-S channels, mostly likely Nav1.7, in the peripheral nervous system produces analgesia by regulating the spontaneous discharge of C-fiber nociceptors.

  5. Novel mutations mapping to the fourth sodium channel domain of Nav1.7 result in variable clinical manifestations of primary erythromelalgia.

    Science.gov (United States)

    Cregg, Roman; Laguda, Bisola; Werdehausen, Robert; Cox, James J; Linley, John E; Ramirez, Juan D; Bodi, Istvan; Markiewicz, Michael; Howell, Kevin J; Chen, Ya-Chun; Agnew, Karen; Houlden, Henry; Lunn, Michael P; Bennett, David L H; Wood, John N; Kinali, Maria

    2013-06-01

    We identified and clinically investigated two patients with primary erythromelalgia mutations (PEM), which are the first reported to map to the fourth domain of Nav1.7 (DIV). The identified mutations (A1746G and W1538R) were cloned and transfected to cell cultures followed by electrophysiological analysis in whole-cell configuration. The investigated patients presented with PEM, while age of onset was very different (3 vs. 61 years of age). Electrophysiological characterization revealed that the early onset A1746G mutation leads to a marked hyperpolarizing shift in voltage dependence of steady-state activation, larger window currents, faster activation kinetics (time-to-peak current) and recovery from steady-state inactivation compared to wild-type Nav1.7, indicating a pronounced gain-of-function. Furthermore, we found a hyperpolarizing shift in voltage dependence of slow inactivation, which is another feature commonly found in Nav1.7 mutations associated with PEM. In silico neuron simulation revealed reduced firing thresholds and increased repetitive firing, both indicating hyperexcitability. The late-onset W1538R mutation also revealed gain-of-function properties, although to a lesser extent. Our findings demonstrate that mutations encoding for DIV of Nav1.7 can not only be linked to congenital insensitivity to pain or paroxysmal extreme pain disorder but can also be causative of PEM, if voltage dependency of channel activation is affected. This supports the view that the degree of biophysical property changes caused by a mutation may have an impact on age of clinical manifestation of PEM. In summary, these findings extent the genotype-phenotype correlation profile for SCN9A and highlight a new region of Nav1.7 that is implicated in PEM. PMID:23292638

  6. A point mutation (L1015F) of the voltage-sensitive sodium channel gene associated with lambda-cyhalothrin resistance in Apolygus lucorum (Meyer-Dür) population from the transgenic Bt cotton field of China.

    Science.gov (United States)

    Zhen, Congai; Gao, Xiwu

    2016-02-01

    In China, the green mirid bug, Apolygus lucorum (Meyer-Dür), has caused severe economic damage to many kinds of crops, especially the cotton and jujubes. Pyrethroid insecticides have been widely used for controlling this pest in the transgenic Bt cotton field. Five populations of A. lucorum collected from cotton crops at different locations in China were evaluated for lambda-cyhalothrin resistance. The results showed that only the population collected from Shandong Province exhibited 30-fold of resistance to lambda-cyhalothrin. Neither PBO nor DEF had obvious synergism when compared the synergistic ratio between SS and RR strain which was originated from the Shandong population. Besides, there were no statistically significant differences (p>0.05) in the carboxylesterase, glutathione S-transferase, or 7-ethoxycoumarin O-deethylase activities between the Shandong population and the laboratory susceptible strain (SS). The full-length sodium channel gene named AlVSSC encoding 2028 amino acids was obtained by RT-PCR and rapid amplification of cDNA ends (RACE). One single point mutation L1015F in the AlVSSC was detected only in the Shandong population. Our results revealed that the L1015F mutation associated with pyrethroid resistance was identified in A. lucorum populations in China. These results will be useful for the rational chemical control of A. lucorum in the transgenic Bt cotton field. PMID:26821662

  7. Potency optimization of Huwentoxin-IV on hNav1.7: a neurotoxin TTX-S sodium-channel antagonist from the venom of the Chinese bird-eating spider Selenocosmia huwena.

    Science.gov (United States)

    Revell, Jefferson D; Lund, Per-Eric; Linley, John E; Metcalfe, Jacky; Burmeister, Nicole; Sridharan, Sudharsan; Jones, Clare; Jermutus, Lutz; Bednarek, Maria A

    2013-06-01

    The spider venom peptide Huwentoxin-IV (HwTx-IV) 1 is a potent antagonist of hNav1.7 (IC50 determined herein as 17 ± 2 nM). Nav1.7 is a voltage-gated sodium channel involved in the generation and conduction of neuropathic and nociceptive pain signals. We prepared a number of HwTx-IV analogs as part of a structure-function study into Nav1.7 antagonism. The inhibitory potency of these analogs was determined by automated electrophysiology and is reported herein. In particular, the native residues Glu(1), Glu(4), Phe(6) and Tyr(33) were revealed as important activity modulators and several peptides bearing mutations in these positions showed significantly increased potency on hNav1.7 while maintaining the original selectivity profile of the wild-type peptide 1 on hNav1.5. Peptide 47 (Gly(1), Gly(4), Trp(33)-HwTx) demonstrated the largest potency increase on hNav1.7 (IC50 0.4 ± 0.1 nM).

  8. Changes in the expression of voltage-gated sodium channels Nav1.3, Nav1.7, Nav1.8, and Nav1.9 in rat trigeminal ganglia following chronic constriction injury.

    Science.gov (United States)

    Xu, Wenhua; Zhang, Jun; Wang, Yuanyin; Wang, Liecheng; Wang, Xuxia

    2016-08-17

    Voltage-gated sodium channels (VGSCs), especially the tetrodotoxin-sensitive Nav1.3 and Nav1.7, and the tetrodotoxin-resistant Nav1.8 and Nav1.9, have been implicated in acute and chronic neuropathic pain. The aim of this study was to investigate the expression of VGSC Nav1.3, Nav1.7, Nav1.8, and Nav1.9 after nerve injury and their roles in the development of trigeminal neuralgia (TN). We used the infraorbital nerve-chronic constriction injury model of TN in the rat. The time course of changes in the mechanical pain threshold was examined. In addition, real-time PCR and double immunofluorescence staining of VGSC α subunits were used to evaluate messenger RNA and protein expression, respectively, in the trigeminal ganglion. Behavioral tests showed that the mechanical pain threshold decreased significantly 4-42 days after surgery and reached the lowest observed value by day 12. Compared with sham-operated controls, we found that trigeminal ganglion in rats subjected to an infraorbital nerve-chronic constriction injury showed upregulation of Nav1.3 and downregulation of Nav1.7, Nav1.8, and Nav1.9 messenger RNA and protein levels. Our findings suggest that VGSC may participate in the regulation of TN. PMID:27327156

  9. Mapping the interaction site for the tarantula toxin hainantoxin-IV (β-TRTX-Hn2a) in the voltage sensor module of domain II of voltage-gated sodium channels.

    Science.gov (United States)

    Cai, Tianfu; Luo, Ji; Meng, Er; Ding, Jiuping; Liang, Songping; Wang, Sheng; Liu, Zhonghua

    2015-06-01

    Peptide toxins often have pharmacological applications and are powerful tools for investigating the structure-function relationships of voltage-gated sodium channels (VGSCs). Although a group of potential VGSC inhibitors have been reported from tarantula venoms, little is known about the mechanism of their interaction with VGSCs. In this study, we showed that hainantoxin-IV (β-TRTX-Hn2a, HNTX-IV in brief), a 35-residue peptide from Ornithoctonus hainana venom, preferentially inhibited rNav1.2, rNav1.3 and hNav1.7 compared with rNav1.4 and hNav1.5. hNav1.7 was the most sensitive to HNTX-IV (IC50∼21nM). In contrast to many other tarantula toxins that affect VGSCs, HNTX-IV at subsaturating concentrations did not alter activation and inactivation kinetics in the physiological range of voltages, while very large depolarization above +70mV could partially activate toxin-bound hNav1.7 channel, indicating that HNTX-IV acts as a gating modifier rather than a pore blocker. Site-directed mutagenesis indicated that the toxin bound to site 4, which was located on the extracellular S3-S4 linker of hNav1.7 domain II. Mutants E753Q, D816N and E818Q of hNav1.7 decreased toxin affinity for hNav1.7 by 2.0-, 3.3- and 130-fold, respectively. In silico docking indicated that a three-toed claw substructure formed by residues with close contacts in the interface between HNTX-IV and hNav1.7 domain II stabilized the toxin-channel complex, impeding movement of the domain II voltage sensor and inhibiting hNav1.7 activation. Our data provide structural details for structure-based drug design and a useful template for the design of highly selective inhibitors of a specific subtype of VGSCs. PMID:25218973

  10. Visible-light-driven TiO{sub 2}/Ag{sub 3}PO{sub 4}/GO heterostructure photocatalyst with dual-channel for photo-generated charges separation

    Energy Technology Data Exchange (ETDEWEB)

    Lu, Bingqing; Ma, Ni; Wang, Yaping; Qiu, Yiwei [Center for Optoelectronics Materials and Devices, Department of Physics, Zhejiang Sci-Tech University, Hangzhou 310018 (China); Hu, Haihua [Zhejiang University City College, Hangzhou 310015 (China); Zhao, Jiahuan; Liang, Dayu; Xu, Sheng; Li, Xiaoyun; Zhu, Zhiyan [Center for Optoelectronics Materials and Devices, Department of Physics, Zhejiang Sci-Tech University, Hangzhou 310018 (China); Cui, Can, E-mail: cancui@zstu.edu.cn [Center for Optoelectronics Materials and Devices, Department of Physics, Zhejiang Sci-Tech University, Hangzhou 310018 (China)

    2015-05-05

    Highlights: • TiO{sub 2}/Ag{sub 3}PO{sub 4}/GO was synthesized with a facile two-step method. • TiO{sub 2}/Ag{sub 3}PO{sub 4}/GO exhibit superior photocatalytic activity and stability. • TiO{sub 2}/Ag{sub 3}PO{sub 4}/GO has dual-channel for photo-generated charges separation. • TiO{sub 2}/Ag{sub 3}PO{sub 4}/GO composite reduces the consumption of Ag. - Abstract: A novel triple-component TiO{sub 2}/Ag{sub 3}PO{sub 4}/graphene oxide (TiO{sub 2}/Ag{sub 3}PO{sub 4}/GO) photocatalyst with dual channels for photo-generated charges separation has been synthesized to improve the photocatalytic activity and stability of Ag{sub 3}PO{sub 4} under visible light. The synthesis involved in-situ growth of Ag{sub 3}PO{sub 4} nanoparticles on GO sheets to form Ag{sub 3}PO{sub 4}/GO, and then deposited TiO{sub 2} nanocrystals on the surface of Ag{sub 3}PO{sub 4} by hydrolysis of Ti(SO{sub 4}){sub 2} at low-temperature hydrothermal condition. The TiO{sub 2}/Ag{sub 3}PO{sub 4}/GO exhibited superior photocatalytic activity and stability to bare Ag{sub 3}PO{sub 4}, TiO{sub 2}/Ag{sub 3}PO{sub 4} and Ag{sub 3}PO{sub 4}/GO in degradation of Rhodamine B and phenol solutions under visible light. It is suggested that the photo-generated electrons in the conduction band of Ag{sub 3}PO{sub 4} can be quickly transferred to GO, while the holes in the valence band of Ag{sub 3}PO{sub 4} can be transferred to the valence band of TiO{sub 2}. The dual transfer channels at the interfaces of TiO{sub 2}/Ag{sub 3}PO{sub 4}/GO result in effective charges separation, leading to enhanced photocatalytic activity and stability. Furthermore, the content of noble metal Ag significantly reduces from 77 wt% in bare Ag{sub 3}PO{sub 4} to 55 wt% in the nanocomposite. The concept of establishing dual channels for charges separation in a triple-component heterostructure provides a promising way to develop photocatalysts with high efficiency.

  11. Direct effect of methylprednisolone on renal sodium and water transport via the principal cells in the kidney

    DEFF Research Database (Denmark)

    Lauridsen, Thomas G; Vase, Henrik; Bech, Jesper N;

    2010-01-01

    Glucocorticoids influence renal concentrating and diluting ability. We tested the hypothesis that methylprednisolone treatment increased renal water and sodium absorption by increased absorption via the aquaporin-2 (AQP2) water channels and the epithelial sodium channels (ENaCs) respectively....

  12. Lack of negatively charged residues at the external mouth of Kir2.2 channels enable the voltage-dependent block by external Mg2+.

    Directory of Open Access Journals (Sweden)

    Junwei Li

    Full Text Available Kir channels display voltage-dependent block by cytosolic cations such as Mg2+ and polyamines that causes inward rectification. In fact, cations can regulate K channel activity from both the extracellular and intracellular sides. Previous studies have provided insight into the up-regulation of Kir channel activity by extracellular K+ concentration. In contrast, extracellular Mg2+ has been found to reduce the amplitude of the single-channel current at milimolar concentrations. However, little is known about the molecular mechanism of Kir channel blockade by external Mg2+ and the relationship between the Mg2+ blockade and activity potentiation by permeant K+ ions. In this study, we applied an interactive approach between theory and experiment. Electrophysiological recordings on Kir2.2 and its mutants were performed by heterologous expression in Xenopus laevis oocytes. Our results confirmed that extracellular Mg2+ could reduce heterologously expressed WT Kir2.2 currents in a voltage dependent manner. The kinetics of inhibition and recovery of Mg2+ exhibit a 3∼4s time constant. Molecular dynamics simulation results revealed a Mg2+ binding site located at the extracellular mouth of Kir2.2 that showed voltage-dependent Mg2+ binding. The mutants, G119D, Q126E and H128D, increased the number of permeant K+ ions and reduced the voltage-dependent blockade of Kir2.2 by extracellular Mg2+.

  13. Anestésicos locais: interação com membranas biológicas e com o canal de sódio voltagem-dependente Local anesthetics: interaction with biological membranes and with the voltage-gated sodium channel

    Directory of Open Access Journals (Sweden)

    Daniele Ribeiro de Araujo

    2008-01-01

    Full Text Available Many theories about the mechanism of action of local anesthetics (LA are described in the literature. Two types of theories can be distinguished: those that focus on the direct effects of LA on their target protein in the axon membranes, i.e. the voltage-gated sodium channel and the ones that take into account the interaction of anesthetic molecules with the lipid membrane phase for the reversible nerve blockage. Since there is a direct correlation between LA hydrophobicity and potency, it is crucial to take this physico-chemical property into account to understand the mechanism of action of LA, be it on the sodium channel protein, lipid(s, or on the whole membrane phase.

  14. Evidence for $s$-channel Single-Top-Quark Production in Events with one Charged Lepton and two Jets at CDF

    CERN Document Server

    Aaltonen, T; Amidei, Dante E; Anastassov, Anton Iankov; Annovi, Alberto; Antos, Jaroslav; Apollinari, Giorgio; Appel, Jeffrey A; Arisawa, Tetsuo; Artikov, Akram Muzafarovich; Asaadi, Jonathan A; Ashmanskas, William Joseph; Auerbach, Benjamin; Aurisano, Adam J; Azfar, Farrukh A; Badgett, William Farris; Bae, Taegil; Barbaro-Galtieri, Angela; Barnes, Virgil E; Barnett, Bruce Arnold; Barria, Patrizia; Bartos, Pavol; Bauce, Matteo; Bedeschi, Franco; Behari, Satyajit; Bellettini, Giorgio; Bellinger, James Nugent; Benjamin, Douglas P; Beretvas, Andrew F; Bhatti, Anwar Ahmad; Bland, Karen Renee; Blumenfeld, Barry J; Bocci, Andrea; Bodek, Arie; Bortoletto, Daniela; Boudreau, Joseph Francis; Boveia, Antonio; Brigliadori, Luca; Bromberg, Carl Michael; Brucken, Erik; Budagov, Ioulian A; Budd, Howard Scott; Burkett, Kevin Alan; Busetto, Giovanni; Bussey, Peter John; Butti, Pierfrancesco; Buzatu, Adrian; Calamba, Aristotle; Camarda, Stefano; Campanelli, Mario; Canelli, Florencia; Carls, Benjamin; Carlsmith, Duncan L; Carosi, Roberto; Carrillo Moreno, Salvador; Casal Larana, Bruno; Casarsa, Massimo; Castro, Andrea; Catastini, Pierluigi; Cauz, Diego; Cavaliere, Viviana; Cavalli-Sforza, Matteo; Cerri, Alessandro; Cerrito, Lucio; Chen, Yen-Chu; Chertok, Maxwell Benjamin; Chiarelli, Giorgio; Chlachidze, Gouram; Cho, Kihyeon; Chokheli, Davit; Clark, Allan Geoffrey; Clarke, Christopher Joseph; Convery, Mary Elizabeth; Conway, John Stephen; Corbo, Matteo; Cordelli, Marco; Cox, Charles Alexander; Cox, David Jeremy; Cremonesi, Matteo; Cruz Alonso, Daniel; Cuevas Maestro, Javier; Culbertson, Raymond Lloyd; D'Ascenzo, Nicola; Datta, Mousumi; de Barbaro, Pawel; Demortier, Luc M; Deninno, Maria Maddalena; D'Errico, Maria; Devoto, Francesco; Di Canto, Angelo; Di Ruzza, Benedetto; Dittmann, Jay Richard; Donati, Simone; D'Onofrio, Monica; Dorigo, Mirco; Driutti, Anna; Ebina, Koji; Edgar, Ryan Christopher; Elagin, Andrey L; Erbacher, Robin D; Errede, Steven Michael; Esham, Benjamin; Farrington, Sinead Marie; Fernández Ramos, Juan Pablo; Field, Richard D; Flanagan, Gene U; Forrest, Robert David; Franklin, Melissa EB; Freeman, John Christian; Frisch, Henry J; Funakoshi, Yujiro; Galloni, Camilla; Garfinkel, Arthur F; Garosi, Paola; Gerberich, Heather Kay; Gerchtein, Elena A; Giagu, Stefano; Giakoumopoulou, Viktoria Athina; Gibson, Karen Ruth; Ginsburg, Camille Marie; Giokaris, Nikos D; Giromini, Paolo; Giurgiu, Gavril A; Glagolev, Vladimir; Glenzinski, Douglas Andrew; Gold, Michael S; Goldin, Daniel; Golossanov, Alexander; Gomez, Gervasio; Gomez-Ceballos, Guillelmo; Goncharov, Maxim T; González López, Oscar; Gorelov, Igor V; Goshaw, Alfred T; Goulianos, Konstantin A; Gramellini, Elena; Grinstein, Sebastian; Grosso-Pilcher, Carla; Group, Robert Craig; Guimaraes da Costa, Joao; Hahn, Stephen R; Han, Ji-Yeon; Happacher, Fabio; Hara, Kazuhiko; Hare, Matthew Frederick; Harr, Robert Francis; Harrington-Taber, Timothy; Hatakeyama, Kenichi; Hays, Christopher Paul; Heinrich, Joel G; Herndon, Matthew Fairbanks; Hocker, James Andrew; Hong, Ziqing; Hopkins, Walter Howard; Hou, Suen Ray; Hughes, Richard Edward; Husemann, Ulrich; Hussein, Mohammad; Huston, Joey Walter; Introzzi, Gianluca; Iori, Maurizio; Ivanov, Andrew Gennadievich; James, Eric B; Jang, Dongwook; Jayatilaka, Bodhitha Anjalike; Jeon, Eun-Ju; Jindariani, Sergo Robert; Jones, Matthew T; Joo, Kyung Kwang; Jun, Soon Yung; Junk, Thomas R; Kambeitz, Manuel; Kamon, Teruki; Karchin, Paul Edmund; Kasmi, Azeddine; Kato, Yukihiro; Ketchum, Wesley Robert; Keung, Justin Kien; Kilminster, Benjamin John; Kim, DongHee; Kim, Hyunsoo; Kim, Jieun; Kim, Min Jeong; Kim, Shin-Hong; Kim, Soo Bong; Kim, Young-Jin; Kim, Young-Kee; Kimura, Naoki; Kirby, Michael H; Knoepfel, Kyle James; Kondo, Kunitaka; Kong, Dae Jung; Konigsberg, Jacobo; Kotwal, Ashutosh Vijay; Kreps, Michal; Kroll, IJoseph; Kruse, Mark Charles; Kuhr, Thomas; Kurata, Masakazu; Laasanen, Alvin Toivo; Lammel, Stephan; Lancaster, Mark; Lannon, Kevin Patrick; Latino, Giuseppe; Lee, Hyun Su; Lee, Jaison; Leo, Sabato; Leone, Sandra; Lewis, Jonathan D; Limosani, Antonio; Lipeles, Elliot David; Lister, Alison; Liu, Hao; Liu, Qiuguang; Liu, Tiehui Ted; Lockwitz, Sarah E; Loginov, Andrey Borisovich; Lucchesi, Donatella; Lucà, Alessandra; Lueck, Jan; Lujan, Paul Joseph; Lukens, Patrick Thomas; Lungu, Gheorghe; Lys, Jeremy E; Lysak, Roman; Madrak, Robyn Leigh; Maestro, Paolo; Malik, Sarah Alam; Manca, Giulia; Manousakis-Katsikakis, Arkadios; Marchese, Luigi Marchese; Margaroli, Fabrizio; Marino, Christopher Phillip; Martínez-Perez, Mario; Matera, Keith; Mattson, Mark Edward; Mazzacane, Anna; Mazzanti, Paolo; McNulty, Ronan; Mehta, Andrew; Mehtala, Petteri; Mesropian, Christina; Miao, Ting; Mietlicki, David John; Mitra, Ankush; Miyake, Hideki; Moed, Shulamit; Moggi, Niccolo; Moon, Chang-Seong; Moore, Ronald Scott; Morello, Michael Joseph; Mukherjee, Aseet; Muller, Thomas; Murat, Pavel A; Mussini, Manuel; Nachtman, Jane Marie; Nagai, Yoshikazu; Naganoma, Junji; Nakano, Itsuo; Napier, Austin; Nett, Jason Michael; Neu, Christopher Carl; Nigmanov, Turgun S; Nodulman, Lawrence J; Noh, Seoyoung; Norniella Francisco, Olga; Oakes, Louise Beth; Oh, Seog Hwan; Oh, Young-do; Oksuzian, Iuri Artur; Okusawa, Toru; Orava, Risto Olavi; Ortolan, Lorenzo; Pagliarone, Carmine Elvezio; Palencia, Jose Enrique; Palni, Prabhakar; Papadimitriou, Vaia; Parker, William Chesluk; Pauletta, Giovanni; Paulini, Manfred; Paus, Christoph Maria Ernst; Phillips, Thomas J; Piacentino, Giovanni M; Pianori, Elisabetta; Pilot, Justin Robert; Pitts, Kevin T; Plager, Charles; Pondrom, Lee G; Poprocki, Stephen; Potamianos, Karolos Jozef; Pranko, Aliaksandr Pavlovich; Prokoshin, Fedor; Ptohos, Fotios K; Punzi, Giovanni; Ranjan, Niharika; Redondo Fernández, Ignacio; Renton, Peter B; Rescigno, Marco; Rimondi, Franco; Ristori, Luciano; Robson, Aidan; Rodriguez, Tatiana Isabel; Rolli, Simona; Ronzani, Manfredi; Roser, Robert Martin; Rosner, Jonathan L; Ruffini, Fabrizio; Ruiz Jimeno, Alberto; Russ, James S; Rusu, Vadim Liviu; Sakumoto, Willis Kazuo; Sakurai, Yuki; Santi, Lorenzo; Sato, Koji; Saveliev, Valeri; Savoy-Navarro, Aurore; Schlabach, Philip; Schmidt, Eugene E; Schwarz, Thomas A; Scodellaro, Luca; Scuri, Fabrizio; Seidel, Sally C; Seiya, Yoshihiro; Semenov, Alexei; Sforza, Federico; Shalhout, Shalhout Zaki; Shears, Tara G; Shepard, Paul F; Shimojima, Makoto; Shochet, Melvyn J; Shreyber-Tecker, Irina; Simonenko, Alexander V; Sliwa, Krzysztof Jan; Smith, John Rodgers; Snider, Frederick Douglas; Song, Hao; Sorin, Maria Veronica; St Denis, Richard Dante; Stancari, Michelle Dawn; Stentz, Dale James; Strologas, John; Sudo, Yuji; Sukhanov, Alexander I; Suslov, Igor M; Takemasa, Ken-ichi; Takeuchi, Yuji; Tang, Jian; Tecchio, Monica; Teng, Ping-Kun; Thom, Julia; Thomson, Evelyn Jean; Thukral, Vaikunth; Toback, David A; Tokar, Stanislav; Tollefson, Kirsten Anne; Tomura, Tomonobu; Tonelli, Diego; Torre, Stefano; Torretta, Donatella; Totaro, Pierluigi; Trovato, Marco; Ukegawa, Fumihiko; Uozumi, Satoru; Velev, Gueorgui; Vellidis, Konstantinos; Vernieri, Caterina; Vidal Marono, Miguel; Vilar Cortabitarte, Rocio; Vizán Garcia, Jesus Manuel; Vogel, Marcelo; Volpi, Guido; Vázquez-Valencia, Elsa Fabiola; Wagner, Peter; Wallny, Rainer S; Wang, Song-Ming; Waters, David S; Wester, William Carl; Whiteson, Daniel O; Wicklund, Arthur Barry; Wilbur, Scott; Williams, Hugh H; Wilson, Jonathan Samuel; Wilson, Peter James; Winer, Brian L; Wittich, Peter; Wolbers, Stephen A; Wolfe, Homer; Wright, Thomas Roland; Wu, Xin; Wu, Zhenbin; Yamamoto, Kazuhiro; Yamato, Daisuke; Yang, Tingjun; Yang, Un-Ki; Yang, Yu Chul; Yao, Wei-Ming; Yeh, Gong Ping; Yi, Kai; Yoh, John; Yorita, Kohei; Yoshida, Takuo; Yu, Geum Bong; Yu, Intae; Zanetti, Anna Maria; Zeng, Yu; Zhou, Chen; Zucchelli, Stefano

    2014-01-01

    We report evidence for $s$-channel single-top-quark production in proton-antiproton collisions at center-of-mass energy $\\sqrt{s}= 1.96~\\mathrm{TeV}$ using a data set that corresponds to an integrated luminosity of $9.4~\\mathrm{fb}^{-1}$ collected by the Collider Detector at Fermilab. We select events consistent with the $s$-channel process including two jets and one leptonically decaying $W$ boson. The observed significance is $3.8$ standard deviations with respect to the background-only prediction. Assuming a top-quark mass of $172.5~\\mathrm{GeV}/c^2$, we measure the $s$-channel cross section to be $1.41^{+0.44}_{-0.42}~\\mathrm{pb}$.

  15. Evidence for s-Channel Single-Top-Quark Production in Events with One Charged Lepton and Two Jets at CDF

    Science.gov (United States)

    Aaltonen, T.; Amerio, S.; Amidei, D.; Anastassov, A.; Annovi, A.; Antos, J.; Apollinari, G.; Appel, J. A.; Arisawa, T.; Artikov, A.; Asaadi, J.; Ashmanskas, W.; Auerbach, B.; Aurisano, A.; Azfar, F.; Badgett, W.; Bae, T.; Barbaro-Galtieri, A.; Barnes, V. E.; Barnett, B. A.; Barria, P.; Bartos, P.; Bauce, M.; Bedeschi, F.; Behari, S.; Bellettini, G.; Bellinger, J.; Benjamin, D.; Beretvas, A.; Bhatti, A.; Bland, K. R.; Blumenfeld, B.; Bocci, A.; Bodek, A.; Bortoletto, D.; Boudreau, J.; Boveia, A.; Brigliadori, L.; Bromberg, C.; Brucken, E.; Budagov, J.; Budd, H. S.; Burkett, K.; Busetto, G.; Bussey, P.; Butti, P.; Buzatu, A.; Calamba, A.; Camarda, S.; Campanelli, M.; Canelli, F.; Carls, B.; Carlsmith, D.; Carosi, R.; Carrillo, S.; Casal, B.; Casarsa, M.; Castro, A.; Catastini, P.; Cauz, D.; Cavaliere, V.; Cavalli-Sforza, M.; Cerri, A.; Cerrito, L.; Chen, Y. C.; Chertok, M.; Chiarelli, G.; Chlachidze, G.; Cho, K.; Chokheli, D.; Clark, A.; Clarke, C.; Convery, M. E.; Conway, J.; Corbo, M.; Cordelli, M.; Cox, C. A.; Cox, D. J.; Cremonesi, M.; Cruz, D.; Cuevas, J.; Culbertson, R.; d'Ascenzo, N.; Datta, M.; de Barbaro, P.; Demortier, L.; Deninno, M.; D'Errico, M.; Devoto, F.; Di Canto, A.; Di Ruzza, B.; Dittmann, J. R.; Donati, S.; D'Onofrio, M.; Dorigo, M.; Driutti, A.; Ebina, K.; Edgar, R.; Elagin, A.; Erbacher, R.; Errede, S.; Esham, B.; Farrington, S.; Fernández Ramos, J. P.; Field, R.; Flanagan, G.; Forrest, R.; Franklin, M.; Freeman, J. C.; Frisch, H.; Funakoshi, Y.; Galloni, C.; Garfinkel, A. F.; Garosi, P.; Gerberich, H.; Gerchtein, E.; Giagu, S.; Giakoumopoulou, V.; Gibson, K.; Ginsburg, C. M.; Giokaris, N.; Giromini, P.; Giurgiu, G.; Glagolev, V.; Glenzinski, D.; Gold, M.; Goldin, D.; Golossanov, A.; Gomez, G.; Gomez-Ceballos, G.; Goncharov, M.; González López, O.; Gorelov, I.; Goshaw, A. T.; Goulianos, K.; Gramellini, E.; Grinstein, S.; Grosso-Pilcher, C.; Group, R. C.; Guimaraes da Costa, J.; Hahn, S. R.; Han, J. Y.; Happacher, F.; Hara, K.; Hare, M.; Harr, R. F.; Harrington-Taber, T.; Hatakeyama, K.; Hays, C.; Heinrich, J.; Herndon, M.; Hocker, A.; Hong, Z.; Hopkins, W.; Hou, S.; Hughes, R. E.; Husemann, U.; Hussein, M.; Huston, J.; Introzzi, G.; Iori, M.; Ivanov, A.; James, E.; Jang, D.; Jayatilaka, B.; Jeon, E. J.; Jindariani, S.; Jones, M.; Joo, K. K.; Jun, S. Y.; Junk, T. R.; Kambeitz, M.; Kamon, T.; Karchin, P. E.; Kasmi, A.; Kato, Y.; Ketchum, W.; Keung, J.; Kilminster, B.; Kim, D. H.; Kim, H. S.; Kim, J. E.; Kim, M. J.; Kim, S. H.; Kim, S. B.; Kim, Y. J.; Kim, Y. K.; Kimura, N.; Kirby, M.; Knoepfel, K.; Kondo, K.; Kong, D. J.; Konigsberg, J.; Kotwal, A. V.; Kreps, M.; Kroll, J.; Kruse, M.; Kuhr, T.; Kurata, M.; Laasanen, A. T.; Lammel, S.; Lancaster, M.; Lannon, K.; Latino, G.; Lee, H. S.; Lee, J. S.; Leo, S.; Leone, S.; Lewis, J. D.; Limosani, A.; Lipeles, E.; Lister, A.; Liu, H.; Liu, Q.; Liu, T.; Lockwitz, S.; Loginov, A.; Lucchesi, D.; Lucà, A.; Lueck, J.; Lujan, P.; Lukens, P.; Lungu, G.; Lys, J.; Lysak, R.; Madrak, R.; Maestro, P.; Malik, S.; Manca, G.; Manousakis-Katsikakis, A.; Marchese, L.; Margaroli, F.; Marino, P.; Martínez, M.; Matera, K.; Mattson, M. E.; Mazzacane, A.; Mazzanti, P.; McNulty, R.; Mehta, A.; Mehtala, P.; Mesropian, C.; Miao, T.; Mietlicki, D.; Mitra, A.; Miyake, H.; Moed, S.; Moggi, N.; Moon, C. S.; Moore, R.; Morello, M. J.; Mukherjee, A.; Muller, Th.; Murat, P.; Mussini, M.; Nachtman, J.; Nagai, Y.; Naganoma, J.; Nakano, I.; Napier, A.; Nett, J.; Neu, C.; Nigmanov, T.; Nodulman, L.; Noh, S. Y.; Norniella, O.; Oakes, L.; Oh, S. H.; Oh, Y. D.; Oksuzian, I.; Okusawa, T.; Orava, R.; Ortolan, L.; Pagliarone, C.; Palencia, E.; Palni, P.; Papadimitriou, V.; Parker, W.; Pauletta, G.; Paulini, M.; Paus, C.; Phillips, T. J.; Piacentino, G.; Pianori, E.; Pilot, J.; Pitts, K.; Plager, C.; Pondrom, L.; Poprocki, S.; Potamianos, K.; Pranko, A.; Prokoshin, F.; Ptohos, F.; Punzi, G.; Ranjan, N.; Redondo Fernández, I.; Renton, P.; Rescigno, M.; Rimondi, F.; Ristori, L.; Robson, A.; Rodriguez, T.; Rolli, S.; Ronzani, M.; Roser, R.; Rosner, J. L.; Ruffini, F.; Ruiz, A.; Russ, J.; Rusu, V.; Sakumoto, W. K.; Sakurai, Y.; Santi, L.; Sato, K.; Saveliev, V.; Savoy-Navarro, A.; Schlabach, P.; Schmidt, E. E.; Schwarz, T.; Scodellaro, L.; Scuri, F.; Seidel, S.; Seiya, Y.; Semenov, A.; Sforza, F.; Shalhout, S. Z.; Shears, T.; Shepard, P. F.; Shimojima, M.; Shochet, M.; Shreyber-Tecker, I.; Simonenko, A.; Sliwa, K.; Smith, J. R.; Snider, F. D.; Song, H.; Sorin, V.; St. Denis, R.; Stancari, M.; Stentz, D.; Strologas, J.; Sudo, Y.; Sukhanov, A.; Suslov, I.; Takemasa, K.; Takeuchi, Y.; Tang, J.; Tecchio, M.; Teng, P. K.; Thom, J.; Thomson, E.; Thukral, V.; Toback, D.; Tokar, S.; Tollefson, K.; Tomura, T.; Tonelli, D.; Torre, S.; Torretta, D.; Totaro, P.; Trovato, M.; Ukegawa, F.; Uozumi, S.; Velev, G.; Vellidis, C.; Vernieri, C.; Vidal, M.; Vilar, R.; Vizán, J.; Vogel, M.; Volpi, G.; Vázquez, F.; Wagner, P.; Wallny, R.; Wang, S. M.; Waters, D.; Wester, W. C.; Whiteson, D.; Wicklund, A. B.; Wilbur, S.; Williams, H. H.; Wilson, J. S.; Wilson, P.; Winer, B. L.; Wittich, P.; Wolbers, S.; Wolfe, H.; Wright, T.; Wu, X.; Wu, Z.; Yamamoto, K.; Yamato, D.; Yang, T.; Yang, U. K.; Yang, Y. C.; Yao, W.-M.; Yeh, G. P.; Yi, K.; Yoh, J.; Yorita, K.; Yoshida, T.; Yu, G. B.; Yu, I.; Zanetti, A. M.; Zeng, Y.; Zhou, C.; Zucchelli, S.; CDF Collaboration

    2014-06-01

    We report evidence for s-channel single-top-quark production in proton-antiproton collisions at center-of-mass energy √s =1.96 TeV using a data set that corresponds to an integrated luminosity of 9.4 fb-1 collected by the Collider Detector at Fermilab. We select events consistent with the s-channel process including two jets and one leptonically decaying W boson. The observed significance is 3.8 standard deviations with respect to the background-only prediction. Assuming a top-quark mass of 172.5 GeV /c2, we measure the s-channel cross section to be 1.41-0.42+0.44 pb.

  16. Evidence for s-channel single-top-quark production in events with one charged lepton and two jets at CDF.

    Science.gov (United States)

    Aaltonen, T; Amerio, S; Amidei, D; Anastassov, A; Annovi, A; Antos, J; Apollinari, G; Appel, J A; Arisawa, T; Artikov, A; Asaadi, J; Ashmanskas, W; Auerbach, B; Aurisano, A; Azfar, F; Badgett, W; Bae, T; Barbaro-Galtieri, A; Barnes, V E; Barnett, B A; Barria, P; Bartos, P; Bauce, M; Bedeschi, F; Behari, S; Bellettini, G; Bellinger, J; Benjamin, D; Beretvas, A; Bhatti, A; Bland, K R; Blumenfeld, B; Bocci, A; Bodek, A; Bortoletto, D; Boudreau, J; Boveia, A; Brigliadori, L; Bromberg, C; Brucken, E; Budagov, J; Budd, H S; Burkett, K; Busetto, G; Bussey, P; Butti, P; Buzatu, A; Calamba, A; Camarda, S; Campanelli, M; Canelli, F; Carls, B; Carlsmith, D; Carosi, R; Carrillo, S; Casal, B; Casarsa, M; Castro, A; Catastini, P; Cauz, D; Cavaliere, V; Cavalli-Sforza, M; Cerri, A; Cerrito, L; Chen, Y C; Chertok, M; Chiarelli, G; Chlachidze, G; Cho, K; Chokheli, D; Clark, A; Clarke, C; Convery, M E; Conway, J; Corbo, M; Cordelli, M; Cox, C A; Cox, D J; Cremonesi, M; Cruz, D; Cuevas, J; Culbertson, R; d'Ascenzo, N; Datta, M; de Barbaro, P; Demortier, L; Deninno, M; D'Errico, M; Devoto, F; Di Canto, A; Di Ruzza, B; Dittmann, J R; Donati, S; D'Onofrio, M; Dorigo, M; Driutti, A; Ebina, K; Edgar, R; Elagin, A; Erbacher, R; Errede, S; Esham, B; Farrington, S; Fernández Ramos, J P; Field, R; Flanagan, G; Forrest, R; Franklin, M; Freeman, J C; Frisch, H; Funakoshi, Y; Galloni, C; Garfinkel, A F; Garosi, P; Gerberich, H; Gerchtein, E; Giagu, S; Giakoumopoulou, V; Gibson, K; Ginsburg, C M; Giokaris, N; Giromini, P; Giurgiu, G; Glagolev, V; Glenzinski, D; Gold, M; Goldin, D; Golossanov, A; Gomez, G; Gomez-Ceballos, G; Goncharov, M; González López, O; Gorelov, I; Goshaw, A T; Goulianos, K; Gramellini, E; Grinstein, S; Grosso-Pilcher, C; Group, R C; Guimaraes da Costa, J; Hahn, S R; Han, J Y; Happacher, F; Hara, K; Hare, M; Harr, R F; Harrington-Taber, T; Hatakeyama, K; Hays, C; Heinrich, J; Herndon, M; Hocker, A; Hong, Z; Hopkins, W; Hou, S; Hughes, R E; Husemann, U; Hussein, M; Huston, J; Introzzi, G; Iori, M; Ivanov, A; James, E; Jang, D; Jayatilaka, B; Jeon, E J; Jindariani, S; Jones, M; Joo, K K; Jun, S Y; Junk, T R; Kambeitz, M; Kamon, T; Karchin, P E; Kasmi, A; Kato, Y; Ketchum, W; Keung, J; Kilminster, B; Kim, D H; Kim, H S; Kim, J E; Kim, M J; Kim, S H; Kim, S B; Kim, Y J; Kim, Y K; Kimura, N; Kirby, M; Knoepfel, K; Kondo, K; Kong, D J; Konigsberg, J; Kotwal, A V; Kreps, M; Kroll, J; Kruse, M; Kuhr, T; Kurata, M; Laasanen, A T; Lammel, S; Lancaster, M; Lannon, K; Latino, G; Lee, H S; Lee, J S; Leo, S; Leone, S; Lewis, J D; Limosani, A; Lipeles, E; Lister, A; Liu, H; Liu, Q; Liu, T; Lockwitz, S; Loginov, A; Lucchesi, D; Lucà, A; Lueck, J; Lujan, P; Lukens, P; Lungu, G; Lys, J; Lysak, R; Madrak, R; Maestro, P; Malik, S; Manca, G; Manousakis-Katsikakis, A; Marchese, L; Margaroli, F; Marino, P; Martínez, M; Matera, K; Mattson, M E; Mazzacane, A; Mazzanti, P; McNulty, R; Mehta, A; Mehtala, P; Mesropian, C; Miao, T; Mietlicki, D; Mitra, A; Miyake, H; Moed, S; Moggi, N; Moon, C S; Moore, R; Morello, M J; Mukherjee, A; Muller, Th; Murat, P; Mussini, M; Nachtman, J; Nagai, Y; Naganoma, J; Nakano, I; Napier, A; Nett, J; Neu, C; Nigmanov, T; Nodulman, L; Noh, S Y; Norniella, O; Oakes, L; Oh, S H; Oh, Y D; Oksuzian, I; Okusawa, T; Orava, R; Ortolan, L; Pagliarone, C; Palencia, E; Palni, P; Papadimitriou, V; Parker, W; Pauletta, G; Paulini, M; Paus, C; Phillips, T J; Piacentino, G; Pianori, E; Pilot, J; Pitts, K; Plager, C; Pondrom, L; Poprocki, S; Potamianos, K; Pranko, A; Prokoshin, F; Ptohos, F; Punzi, G; Ranjan, N; Redondo Fernández, I; Renton, P; Rescigno, M; Rimondi, F; Ristori, L; Robson, A; Rodriguez, T; Rolli, S; Ronzani, M; Roser, R; Rosner, J L; Ruffini, F; Ruiz, A; Russ, J; Rusu, V; Sakumoto, W K; Sakurai, Y; Santi, L; Sato, K; Saveliev, V; Savoy-Navarro, A; Schlabach, P; Schmidt, E E; Schwarz, T; Scodellaro, L; Scuri, F; Seidel, S; Seiya, Y; Semenov, A; Sforza, F; Shalhout, S Z; Shears, T; Shepard, P F; Shimojima, M; Shochet, M; Shreyber-Tecker, I; Simonenko, A; Sliwa, K; Smith, J R; Snider, F D; Song, H; Sorin, V; St Denis, R; Stancari, M; Stentz, D; Strologas, J; Sudo, Y; Sukhanov, A; Suslov, I; Takemasa, K; Takeuchi, Y; Tang, J; Tecchio, M; Teng, P K; Thom, J; Thomson, E; Thukral, V; Toback, D; Tokar, S; Tollefson, K; Tomura, T; Tonelli, D; Torre, S; Torretta, D; Totaro, P; Trovato, M; Ukegawa, F; Uozumi, S; Velev, G; Vellidis, C; Vernieri, C; Vidal, M; Vilar, R; Vizán, J; Vogel, M; Volpi, G; Vázquez, F; Wagner, P; Wallny, R; Wang, S M; Waters, D; Wester, W C; Whiteson, D; Wicklund, A B; Wilbur, S; Williams, H H; Wilson, J S; Wilson, P; Winer, B L; Wittich, P; Wolbers, S; Wolfe, H; Wright, T; Wu, X; Wu, Z; Yamamoto, K; Yamato, D; Yang, T; Yang, U K; Yang, Y C; Yao, W-M; Yeh, G P; Yi, K; Yoh, J; Yorita, K; Yoshida, T; Yu, G B; Yu, I; Zanetti, A M; Zeng, Y; Zhou, C; Zucchelli, S

    2014-06-13

    We report evidence for s-channel single-top-quark production in proton-antiproton collisions at center-of-mass energy sqrt[s] = 1.96 TeV using a data set that corresponds to an integrated luminosity of 9.4 fb(-1) collected by the Collider Detector at Fermilab. We select events consistent with the s-channel process including two jets and one leptonically decaying W boson. The observed significance is 3.8 standard deviations with respect to the background-only prediction. Assuming a top-quark mass of 172.5 GeV/c(2), we measure the s-channel cross section to be 1.41(-0.42)(+0.44) pb.

  17. Axon Membrane Skeleton Structure is Optimized for Coordinated Sodium Propagation

    CERN Document Server

    Zhang, Yihao; Li, He; Tzingounis, Anastasios V; Lykotrafitis, George

    2016-01-01

    Axons transmit action potentials with high fidelity and minimal jitter. This unique capability is likely the result of the spatiotemporal arrangement of sodium channels along the axon. Super-resolution microscopy recently revealed that the axon membrane skeleton is structured as a series of actin rings connected by spectrin filaments that are held under entropic tension. Sodium channels also exhibit a periodic distribution pattern, as they bind to ankyrin G, which associates with spectrin. Here, we elucidate the relationship between the axon membrane skeleton structure and the function of the axon. By combining cytoskeletal dynamics and continuum diffusion modeling, we show that spectrin filaments under tension minimize the thermal fluctuations of sodium channels and prevent overlap of neighboring channel trajectories. Importantly, this axon skeletal arrangement allows for a highly reproducible band-like activation of sodium channels leading to coordinated sodium propagation along the axon.

  18. Mutation of neuronal channels of sodium and chloride associated with generalized epilepsy with febrile seizures plus (gefs+ Mutaciones de los canales neuronales de sodio y cloro asociadas a epilepsia generalizada con convulsiones febriles plus

    Directory of Open Access Journals (Sweden)

    Gabriel Bedoya Berrío

    2004-02-01

    Full Text Available Generalized Epilepsy with Febrile Seizures Plus (GEFS+ is a frequent entity characterized by generalized seizures with a wide phenotypic variety; the age of onset is 3 months and it persists beyond 6 years. Seizures may or may not be induced by fever. The disease has shown an autosomic dominant trait, incomplete penetrance and association with mutations on the genes that encode voltage-dependent sodium channels and the chloride neuronal channels on the central nervous system. The wide spectrum GEFS+ phenotype has been related with others entities such as Severe Myoclonic Epilepsy of Infancy (SMEI and Intractable Childhood Epilepsy with Frequent Generalized Tonic-Clonic Seizures (ICEGTC; they have mutations in common with GEFS+ according to several recently published articles. This review compiles up to date information about EGCF+ with the aim of giving the reader a knowledge of this entity and of its association with mutations that participate in its pathogenesis. La Epilepsia Generalizada Con Convulsiones Febriles Plus (EGCF+, es una entidad relativamente común. Se caracteriza por convulsiones de tipo generalizado con una gran variabilidad fenotípica; se presenta desde los 3 meses de edad y persiste más allá de los 6 años; las convulsiones pueden ser precipitadas por fiebre pero se presentan también sin ella. La enfermedad se ha asociado a herencia autosómica dominante con penetrancia incompleta, en la que intervienen mutaciones de los genes que codifican los canales iónicos de sodio dependientes del voltaje y de los canales iónicos de cloro en las neuronas del Sistema Nervioso Central (SNC. El amplio fenotipo de la EGCF+ se ha encontrado en asociación con otras entidades como la Epilepsia Mioclónica Severa del Lactante (EMSL y la Epilepsia Generalizada Tónico-Clónica Intratable de la Infancia (EGTCII, las cuales han presentado mutaciones comunes con las de la EGCF+, según informes recientemente publicados. Esta revisi

  19. Association between Three Mutations, F1565C, V1023G and S996P, in the Voltage-Sensitive Sodium Channel Gene and Knockdown Resistance in Aedes aegypti from Yogyakarta, Indonesia

    Directory of Open Access Journals (Sweden)

    Juli Rochmijati Wuliandari

    2015-07-01

    Full Text Available Mutations in the voltage-sensitive sodium channel gene (Vssc have been identified in Aedes aegypti and some have been associated with pyrethroid insecticide resistance. Whether these mutations cause resistance, alone or in combination with other alleles, remains unclear, but must be understood if mutations are to become markers for resistance monitoring. We describe High Resolution Melt (HRM genotyping assays for assessing mutations found in Ae. aegypti in Indonesia (F1565C, V1023G, S996P and use them to test for associations with pyrethroid resistance in mosquitoes from Yogyakarta, a city where insecticide use is widespread. Such knowledge is important because Yogyakarta is a target area for releases of Wolbachia-infected mosquitoes with virus-blocking traits for dengue suppression. We identify three alleles across Yogyakarta putatively linked to resistance in previous research. By comparing resistant and susceptible mosquitoes from bioassays, we show that the 1023G allele is associated with resistance to type I and type II pyrethroids. In contrast, F1565C homozygotes were rare and there was only a weak association between individuals heterozygous for the mutation and resistance to a type I pyrethroid. As the heterozygote is expected to be incompletely recessive, it is likely that this association was due to a different resistance mechanism being present. A resistance advantage conferred to V1023G homozygotes through addition of the S996P allele in the homozygous form was suggested for the Type II pyrethroid, deltamethrin. Screening of V1023G and S996P should assist resistance monitoring in Ae. aegypti from Yogyakarta, and these mutations should be maintained in Wolbachia strains destined for release in this city to ensure that these virus-blocking strains of mosquitoes are not disadvantaged, relative to resident populations.

  20. Congenital insensitivity to pain: Fracturing without apparent skeletal pathobiology caused by an autosomal dominant, second mutation in SCN11A encoding voltage-gated sodium channel 1.9.

    Science.gov (United States)

    Phatarakijnirund, Voraluck; Mumm, Steven; McAlister, William H; Novack, Deborah V; Wenkert, Deborah; Clements, Karen L; Whyte, Michael P

    2016-03-01

    Congenital insensitivity to pain (CIP) comprises the rare heritable disorders without peripheral neuropathy that feature inability to feel pain. Fracturing and joint destruction are common complications, but lack detailed studies of mineral and skeletal homeostasis and bone histology. In 2013, discovery of a heterozygous gain-of-function mutation in SCN11A encoding voltage-gated sodium channel 1.9 (Nav1.9) established a distinctive CIP in three unrelated patients who suffered multiple painless fractures, self-inflicted mutilation, chronic diarrhea, and hyperhidrosis. Here, we studied a mother and two children with CIP by physical examination, biochemical testing, radiological imaging including DXA, iliac crest histology, and mutation analysis. She suffered fractures primarily of her lower extremities beginning at age two years, and had Charcot deformity of both ankles and joint hypermobility. Nerve conduction velocity together with electromyography were normal. Her children had recurrent major fractures beginning in early childhood, joint hypermobility, and chronic diarrhea. She had an excoriated external nare, and both children had hypertrophic scars from scratching. Skin collagen studies were normal. Radiographs revealed fractures and deformities. However, lumbar spine and total hip BMD Z-scores, biochemical parameters of mineral and skeletal homeostasis, and iliac crest histology of the mother (after in vivo tetracycline labeling) were normal. Genomic DNA from the children revealed a unique heterozygous missense mutation in exon 23 (c.3904C>T, p.Leu1302Phe) of SCN11A that is absent in SNP databases and alters an evolutionarily conserved amino acid. This autosomal dominant CIP reflects the second gain-of-function mutation of SCN11A. Perhaps joint hypermobility is an unreported feature. How mutation of Nav1.9 causes fracturing remains unexplained. Lack of injury awareness is typically offered as the reason, and was supported by our unremarkable biochemical

  1. Epilepsy-Related Slack Channel Mutants Lead to Channel Over-Activity by Two Different Mechanisms.

    Science.gov (United States)

    Tang, Qiong-Yao; Zhang, Fei-Fei; Xu, Jie; Wang, Ran; Chen, Jian; Logothetis, Diomedes E; Zhang, Zhe

    2016-01-01

    Twelve sodium-activated potassium channel (KCNT1, Slack) genetic mutants have been identified from severe early-onset epilepsy patients. The changes in biophysical properties of these mutants and the underlying mechanisms causing disease remain elusive. Here, we report that seven of the 12 mutations increase, whereas one mutation decreases, the channel's sodium sensitivity. Two of the mutants exhibit channel over-activity only when the intracellular Na(+) ([Na(+)]i) concentration is ∼80 mM. In contrast, single-channel data reveal that all 12 mutants increase the maximal open probability (Po). We conclude that these mutant channels lead to channel over-activity predominantly by increasing the ability of sodium binding to activate the channel, which is indicated by its maximal Po. The sodium sensitivity of these epilepsy causing mutants probably determines the [Na(+)]i concentration at which these mutants exert their pathological effects. PMID:26725113

  2. Putative resolution of the EEEE selectivity paradox in L-type Ca2+ and bacterial Na+ biological ion channels

    Science.gov (United States)

    Kaufman, I. Kh; Luchinsky, D. G.; Gibby, W. A. T.; McClintock, P. V. E.; Eisenberg, R. S.

    2016-05-01

    The highly selective permeation of ions through biological ion channels can be described and explained in terms of fluctuational dynamics under the influence of powerful electrostatic forces. Hence valence selectivity, e.g. between Ca2+ and Na+ in calcium and sodium channels, can be described in terms of ionic Coulomb blockade, which gives rise to distinct conduction bands and stop-bands as the fixed negative charge Q f at the selectivity filter of the channel is varied. This picture accounts successfully for a wide range of conduction phenomena in a diversity of ion channels. A disturbing anomaly, however, is that what appears to be the same electrostatic charge and structure (the so-called EEEE motif) seems to select Na+ conduction in bacterial channels but Ca2+ conduction in mammalian channels. As a possible resolution of this paradox it is hypothesised that an additional charged protein residue on the permeation path of the mammalian channel increases |{{Q}f}| by e, thereby altering the selectivity from Na+ to Ca2+. Experiments are proposed that will enable the hypothesis to be tested.

  3. Test Your Sodium Smarts

    Science.gov (United States)

    ... You may be surprised to learn how much sodium is in many foods. Sodium, including sodium chloride ... foods with little or no salt. Test your sodium smarts by answering these 10 questions about which ...

  4. Sodium and potassium conductance changes during a membrane action potential.

    Science.gov (United States)

    Bezanilla, F; Rojas, E; Taylor, R E

    1970-12-01

    1. A method for turning a membrane potential control system on and off in less than 10 musec is described. This method was used to record membrane currents in perfused giant axons from Dosidicus gigas and Loligo forbesi after turning on the voltage clamp system at various times during the course of a membrane action potential.2. The membrane current measured just after the capacity charging transient was found to have an almost linear relation to the controlled membrane potential.3. The total membrane conductance taken from these current-voltage curves was found to have a time course during the action potential similar to that found by Cole & Curtis (1939).4. The instantaneous current voltage curves were linear enough to make it possible to obtain a good estimate of the individual sodium and potassium channel conductances, either algebraically or by clamping to the sodium, or potassium, reversal potentials. Good general agreement was obtained with the predictions of the Hodgkin-Huxley equations.5. We consider these results to constitute the first direct experimental demonstration of the conductance changes to sodium and potassium during the course of an action potential. PMID:5505231

  5. 海南捕鸟蛛毒素-Ⅵ,一种新型的抑制昆虫电压门控钠通道失活的狼蛛神经毒素%Hainantoxin-Ⅵ, A Novel Tarantula Neurotoxin Inhibiting Insect Voltage-gated Sodium Channel Inactivation

    Institute of Scientific and Technical Information of China (English)

    王瑞兰; 潘建议; 肖玉成; 王美迟; 梁宋平

    2008-01-01

    The neurotoxin peptide, hainantoxin-Ⅵ (HNTX- Ⅵ), has been isolated from the venom of Chinese tarantula Ornithoconus hainana by a combination of ion exchange chromatography and reverse phase HPLC. The toxin was found to contain 34 amino acid residues with 6 conserved cysteine residues. The effects of HNTX-VI on voltage-gated sodium channels were studied via whole-cell patch clamp techniques. Although several inhibitors of mammalian neuronal sodium channel activation (hainantoxin Ⅰ-Ⅴ) had been characterized from the same venom, the present study indicated that HNTX-Ⅵ had the ability to slow the inactivation kinetics of the sodium channels in Cockroach Periplaneta Americana dorsal unpaired median (DUM) neurons in a similar manner to δ-atractoxins. After HNTX-Ⅵ treatment, steady-state sodium channel inactivation became incomplete, leading to a non-inactivating component at potentials more positive than - 55 mV. The novel function of the tarantula toxin HNTX-Ⅵ not only supplies a useful tool for exploring the gating mechanisms of sodium channels but also provides theoretical foundations for exploiting novel and safe insecticides.%通过阳离子交换和反相HPLC柱层析从海南捕鸟蛛(Ornithoconus hainana)粗毒中分离到一种新型的神经毒素,海南捕鸟蛛毒素-Ⅵ(HNTX-Ⅵ),由34个氨基酸残基组成,含有6个保守的半胱氨酸残基.运用全细胞膜片钳技术,研究了HNTX-Ⅵ对电压门控钠通道的影响.先前从海南捕鸟蛛粗毒中分离到的几种毒素,具有抑制哺乳动物钠通道激活的特性.本文研究结果表明,HNTX-Ⅵ能以类似于δ-atractoxins作用方式延缓蜚蠊背侧不成对中间(dorsal unpaired median,DUM)神经细胞的钠通道的失活,且导致钠通道稳态失活变得不完全,在预钳制电压大于-55 mV时形成不完全失活结构.HNTX-Ⅵ的这种新的功能不仅为探索钠通道的门控机制提供了有用的工具,也为开发新的安全的杀虫剂提供理论基础.

  6. Gd3+ and calcium sensitive, sodium leak currents are features of weak membrane-glass seals in patch clamp recordings.

    Directory of Open Access Journals (Sweden)

    Adrienne N Boone

    Full Text Available The properties of leaky patch currents in whole cell recording of HEK-293T cells were examined as a means to separate these control currents from expressed sodium and calcium leak channel currents from snail NALCN leak channels possessing both sodium (EKEE and calcium (EEEE selectivity filters. Leak currents were generated by the weakening of gigaohm patch seals by artificial membrane rupture using the ZAP function on the patch clamp amplifier. Surprisingly, we found that leak currents generated from the weakened membrane/glass seal can be surprisingly stable and exhibit behavior that is consistent with a sodium leak current derived from an expressible channel. Leaky patch currents differing by 10 fold in size were similarly reduced in size when external sodium ions were replaced with the large monovalent ion NMDG+. Leaky patch currents increased when external Ca2+ (1.2 mM was lowered to 0.1 mM and were inhibited (>40% to >90% with 10 µM Gd3+, 100 µM La3+, 1 mM Co2+ or 1 mM Cd2+. Leaky patch currents were relatively insensitive (<30% to 1 mM Ni2+ and exhibited a variable amount of block with 1 mM verapamil and were insensitive to 100 µM mibefradil or 100 µM nifedipine. We hypothesize that the rapid changes in leak current size in response to changing external cations or drugs relates to their influences on the membrane seal adherence and the electro-osmotic flow of mobile cations channeling in crevices of a particular pore size in the interface between the negatively charged patch electrode and the lipid membrane. Observed sodium leak conductance currents in weak patch seals are reproducible between the electrode glass interface with cell membranes, artificial lipid or Sylgard rubber.

  7. 从微信收费之争看瓶颈垄断的反垄断法规制%Discussing the Bottleneck Monopoly Antitrust Regulation Viewing from the Dispute of the Micro-channel Charge

    Institute of Scientific and Technical Information of China (English)

    张积储

    2013-01-01

    Recently , the "micro-channel charge dispute"between three major telecom operators and Tencent set off a wave of the Internet economy monopoly .In the network economy era , the bottleneck monopoly of the economy is becoming more and more , China's "anti-monopoly law"should make corresponding regulations aganist the bottle-neck monopoly , standardize the market behavior of dominant companies .This study takes the dispute of micro-channel charge as clues to introduce the concept of monopoly bottlenecks , analyzes the regulation against the bottle-neck monopoly , highlights the necessity of regulation .Finally, some legislation recommandations are proposed for regulating the bottleneck monopoly .%日前,电信三大运营商与腾讯的“微信收费之争”掀起了网络经济的垄断浪潮。在网络经济的时代下,瓶颈垄断经济越来越多,我国《反垄断法》应该对这种瓶颈垄断行为作出相应的规定,规范优势企业的市场行为。将以微信收费的争端为线索,引出瓶颈垄断的概念,浅析我国垄断法对瓶颈垄断的规制,突出瓶颈垄断行为应受规制的必要性,并提出瓶颈垄断反垄断法规制的立法建议。

  8. mTORC2信号通路调节上皮细胞钠通道的研究进展%Research advance of mTORC2 signaling pathway in regulation of epithelial sodium channel

    Institute of Scientific and Technical Information of China (English)

    瞿利元; 王导新

    2013-01-01

    Mammalian target of rapamycin (mTO